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• Sequencing data from triple-negative breast cancer tumors

  Autoimmunity and anti-cancer immunity lie on the same biological continuum1,2, but their link remains obscure. The paraneoplastic neurological syndrome anti-NMDA receptor (NMDAR) encephalitis (ANRE) is a paradigm for their connectivity3 given that intratumoral NMDAR expression correlates with the generation of anti-NMDAR antibodies4,5. Here, we verify ectopic expression of GluN1 and GluN2B NMDAR sub-units in triple-negative breast cancer (TNBC)6 and model this using orthotopic TNBC tumors with inducible expression of GluN1-GluN2B NMDARs. We show that NMDAR expression is sufficient to induce B cell recruitment and their affinity maturation, consistent with an integrated adaptive immune response. Reconstruction of extended intratumoral B cell phylogenies and cryo-EM structural analyses demonstrated that affinity-matured hypermutated and class-switched antibodies emerged from pre-existing germline-configuration lower-affinity anti-NMDAR antibodies. Distinct matured antibodies targeted specific epitopes and induced conformational rearrangements within the NMDAR amino-terminal domain, predictive of their functional effects, ranging from inhibition to potentiation. Passive transfer of an NMDAR-potentiating antibody caused autonomic dysregulation and lowered the seizure threshold in healthy female mice, recapitulating key diagnostic criteria of ANRE4,5. We further identify a correlation between intratumoral NMDAR expression and anti-NMDAR antibody titers in TNBC patients. Taken together, our data establish a direct connection between intratumoral NMDAR expression, antibody maturation, and the onset of autoimmunity. These findings suggest that germline-encoded anti-NMDAR antibodies contribute to immune surveillance but can also trigger autoimmune disease upon maturation, revealing a mechanistic tradeoff between cancer immunity and neurotoxicity.

  Study EGAS50000001585

• Sequencing data from triple-negative breast cancer tumors

  Autoimmunity and anti-cancer immunity lie on the same biological continuum1,2, but their link remains obscure. The paraneoplastic neurological syndrome anti-NMDA receptor (NMDAR) encephalitis (ANRE) is a paradigm for their connectivity3 given that intratumoral NMDAR expression correlates with the generation of anti-NMDAR antibodies4,5. Here, we verify ectopic expression of GluN1 and GluN2B NMDAR sub-units in triple-negative breast cancer (TNBC)6 and model this using orthotopic TNBC tumors with inducible expression of GluN1-GluN2B NMDARs. We show that NMDAR expression is sufficient to induce B cell recruitment and their affinity maturation, consistent with an integrated adaptive immune response. Reconstruction of extended intratumoral B cell phylogenies and cryo-EM structural analyses demonstrated that affinity-matured hypermutated and class-switched antibodies emerged from pre-existing germline-configuration lower-affinity anti-NMDAR antibodies. Distinct matured antibodies targeted specific epitopes and induced conformational rearrangements within the NMDAR amino-terminal domain, predictive of their functional effects, ranging from inhibition to potentiation. Passive transfer of an NMDAR-potentiating antibody caused autonomic dysregulation and lowered the seizure threshold in healthy female mice, recapitulating key diagnostic criteria of ANRE4,5. We further identify a correlation between intratumoral NMDAR expression and anti-NMDAR antibody titers in TNBC patients. Taken together, our data establish a direct connection between intratumoral NMDAR expression, antibody maturation, and the onset of autoimmunity. These findings suggest that germline-encoded anti-NMDAR antibodies contribute to immune surveillance but can also trigger autoimmune disease upon maturation, revealing a mechanistic tradeoff between cancer immunity and neurotoxicity.

  Study EGAS50000001598

• GeoMx DSP of NGS mRNA expression in pre-treatment biopsies from patients with metastatic triple-negative breast cancer treated with PARP inhibitors.

  This dataset contains GeoMx digital spatial profiling (DSP) data from 12 FFPE pre-treatment biopsies of metastatic HR-altered breast cancer patients subsequently treated with PARP inhibitors (Olaparib or Talazoparib). Samples were collected from primary breast tumors (n=7) and metastatic sites including lymph nodes (n=2), bone (n=2), and brain (n=1). Tissue sections were stained for pan-cytokeratin (PANCK) to selectively profile tumor cells, with NGS-based transcriptome data generated for both PANCK+ and PANCK- regions. The dataset includes raw data files (176 fastq files) along with clinical annotations.

  Dataset EGAD50000001932

• SCANDARE HNSCC 3' Tag RNA-seq

  SCANDARE (NCT03017573) is a multicentric biobanking study, enrolling adult patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), triple negative breast cancer (TNBC), ovarian and cervical cancer. Tumor tissue and blood samples are collected at several time points during patient's journey, including at diagnosis, post-neoadjuvant chemotherapy in case of neoadjuvant treatment, at surgery, at recurrence and at disease progression following treatment initiated at recurrence. Since its launch in 2017 at Institut Curie, SCANDARE has enabled the longitudinal collection and preservation of samples for in-depth analyses. Here, we describe molecular alterations in 264 FFPE samples at baseline from 90 HNSCC patients using 3'-tag RNA-seq technology, with FASTQ files deposited in the dataset.

  Dataset EGAD50000001655

• SCANDARE TNBC WES data

  SCANDARE (NCT03017573) is a multicentric biobanking study, enrolling adult patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), triple negative breast cancer (TNBC), ovarian and cervical cancer. Tumor tissue and blood samples are collected at several time points during patient's journey, including at diagnosis, post-neoadjuvant chemotherapy in case of neoadjuvant treatment, at surgery, at recurrence and at disease progression following treatment initiated at recurrence. Since its launch in 2017 at Institut Curie, SCANDARE has enabled the longitudinal collection and preservation of samples for in-depth analyses. Here, we describe molecular alterations in 247 frozen samples at baseline and 138 germline DNA from 139 TNBC patients using WES technology, with FASTQ files deposited in the dataset.

  Dataset EGAD50000001661

• SCANDARE TNBC WGS data

  SCANDARE (NCT03017573) is a multicentric biobanking study, enrolling adult patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), triple negative breast cancer (TNBC), ovarian and cervical cancer. Tumor tissue and blood samples are collected at several time points during patient's journey, including at diagnosis, post-neoadjuvant chemotherapy in case of neoadjuvant treatment, at surgery, at recurrence and at disease progression following treatment initiated at recurrence. Since its launch in 2017 at Institut Curie, SCANDARE has enabled the longitudinal collection and preservation of samples for in-depth analyses. Here, we describe molecular alterations in 108 FFPE samples at baseline and 108 germline DNA from 108 TNBC patients using WGS technology, with FASTQ files deposited in the dataset.

  Dataset EGAD50000001662

• SCANDARE TNBC shallow WGS data

  SCANDARE (NCT03017573) is a multicentric biobanking study, enrolling adult patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), triple negative breast cancer (TNBC), ovarian and cervical cancer. Tumor tissue and blood samples are collected at several time points during patient's journey, including at diagnosis, post-neoadjuvant chemotherapy in case of neoadjuvant treatment, at surgery, at recurrence and at disease progression following treatment initiated at recurrence. Since its launch in 2017 at Institut Curie, SCANDARE has enabled the longitudinal collection and preservation of samples for in-depth analyses. Here, we describe molecular alterations in 251 frozen samples at baseline from 143 TNBC patients using shallow WGS technology, with FASTQ files deposited in the dataset.

  Dataset EGAD50000001849

• SCANDARE ovarian WES data

  SCANDARE (NCT03017573) is a multicentric biobanking study, enrolling adult patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), triple negative breast cancer (TNBC), ovarian and cervical cancer. Tumor tissue and blood samples are collected at several time points during patient's journey, including at diagnosis, post-neoadjuvant chemotherapy in case of neoadjuvant treatment, at surgery, at recurrence and at disease progression following treatment initiated at recurrence. Since its launch in 2017 at Institut Curie, SCANDARE has enabled the longitudinal collection and preservation of samples for in-depth analyses. Here, we describe molecular alterations in 91 frozen samples (n = 53 at baseline, n = 31 Post-NAC, n= 7 Recurrence, and n = 62 germline DNA) from 64 ovarian cancer patients using WES technology, with FASTQ files deposited in the dataset.

  Dataset EGAD50000001658

• SCANDARE TNBC transcriptomics data

  SCANDARE (NCT03017573) is a multicentric biobanking study, enrolling adult patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), triple negative breast cancer (TNBC), ovarian and cervical cancer. Tumor tissue and blood samples are collected at several time points during patient's journey, including at diagnosis, post-neoadjuvant chemotherapy in case of neoadjuvant treatment, at surgery, at recurrence and at disease progression following treatment initiated at recurrence. Since its launch in 2017 at Institut Curie, SCANDARE has enabled the longitudinal collection and preservation of samples for in-depth analyses. Here, we describe molecular alterations in 124 frozen samples (n=84 at baseline and n=40 paired at post-NAC surgery) from 91 TNBC patients using total RNAseq technology, with FASTQ files deposited in the dataset.

  Dataset EGAD50000001416

• Functional Mapping of AKT Signaling and Biomarkers of Response From the FAIRLANE Trial of Neoadjuvant Ipatasertib Plus Paclitaxel for Triple-Negative Breast Cancer

  Purpose: Despite extensive genomic and transcriptomic profiling, it remains unknown how signaling pathways are differentially activated and how tumors are differentially sensitized to certain perturbations. Here, we aim to characterize AKT signaling activity and its association with other genomic or immunohistochemistry-based PI3K/AKT pathway biomarkers as well as the clinical activity of ipatasertib (AKT inhibitor) in the FAIRLANE trial. Experimental Design: In FAIRLANE, 151 patients with early triple-negative breast cancer were randomized 1:1 to receive paclitaxel with ipatasertib or placebo for 12 weeks prior to surgery. Adding ipatasertib did not increase pathologic complete response rate and numerically improved overall response rate by magnetic resonance imaging (MRI). We used reverse-phase protein microarrays (RPPA) to examine the total level and/or phosphorylation states of over 100 proteins in various signaling or cell processes including PI3K/AKT and mTOR signaling. 125 baseline and 127 on-treatment samples were evaluable by RPPA, with 110 paired samples at both time points. Results: Tumors with genomic/protein alterations in PIK3CA/AKT1/PTEN were associated with higher levels of AKT phosphorylation. In addition, phosphorylated(p)AKT levels exhibited a significant association with enriched clinical benefit of ipatasertib, and identified patients who received benefit in the absence of PIK3CA/AKT1/PTEN alterations. Ipatasertib treatment led to a down-regulation of AKT/mTORC1 signaling, which was more pronounced among the tumors with PIK3CA/AKT1/PTEN alterations or among the responders to the treatment. Conclusions: We showed that the high baseline pAKT levels are associated with the alterations of PI3K/AKT pathway components and enriched benefit of ipatasertib in TNBC.

  Study EGAS00001005892

• Single-cell decoding of drug induced transcriptomic reprogramming in triple negative breast cancers

  Background The encoding of cell intrinsic drug resistance states in breast cancer reflects the contributions of genomic and non-genomic variations and requires accurate estimation of clonal fitness from co-measurement of transcriptomic and genomic data. Somatic copy number (CN) variation is the dominant mutational mechanism leading to transcriptional variation and notably contributes to platinum chemotherapy resistance cell states. Here, we deploy time series measurements of triple negative breast cancer (TNBC) single-cell transcriptomes, along with co-measured single-cell CN fitness, identifying genomic and transcriptomic mechanisms in drug associated transcriptional cell states. Results We present scRNA-seq data (53,641 filtered cells) from serial passaging TNBC patient-derived xenograft (PDX) experiments spanning 2.5 years, matched with genomic single-cell CN data from the same samples. Our findings reveal distinct clonal responses within TNBC tumors exposed to platinum. Clones with high drug fitness undergo clonal sweeps and show subtle transcriptional reversion, while those with weak fitness exhibit dynamic transcription upon drug withdrawal. Pathway analysis highlights convergence on epithelial-mesenchymal transition and cytokine signaling, associated with resistance. Furthermore, pseudotime analysis demonstrates hysteresis in transcriptional reversion, indicating generation of new intermediate transcriptional states upon platinum exposure. Conclusions Within a polyclonal tumor, clones with strong genotype-associated fitness under platinum remained fixed, minimizing transcriptional reversion upon drug withdrawal. Conversely, clones with weaker fitness display non-genomic transcriptional plasticity. This suggests CN-associated and CN-independent transcriptional states could both contribute to platinum resistance. The dominance of genomic or non-genomic mechanisms within polyclonal tumors has implications for drug sensitivity, restoration and re-treatment strategies.

  Study EGAS00001007242

• Scalable whole-genome single-cell library preparation without pre-amplification

  Single-cell genomics is critical for understanding cellular heterogeneity in cancer, but existing library preparation methods are expensive, require sample preamplification and introduce coverage bias. Here we describe direct library preparation (DLP), a robust, scalable, and high-fidelity method that uses nanoliter-volume transposition reactions for single-cell whole-genome library preparation without preamplification. We examined 782 cells from cell lines and triple-negative breast xenograft tumors. Low-depth sequencing, compared with existing methods, revealed greater coverage uniformity and more reliable detection of copy-number alterations. Using phylogenetic analysis, we found minor xenograft subpopulations that were undetectable by bulk sequencing, as well as dynamic clonal expansion and diversification between passages. Merging single-cell genomes in silico, we generated "bulk-equivalent" genomes with high depth and uniform coverage. Thus, low-depth sequencing of DLP libraries may provide an attractive replacement for conventional bulk sequencing methods, permitting analysis of copy number at the cell level and of other genomic variants at the population level.

  Study EGAS00001002170

• Genomic Studies of Gilles de la Tourette Syndrome

  This study consists of three components. The first component includes genome-wide association study (GWAS) data on 695 TS cases and 198 ancestry matched controls from the first TS GWAS of 1285 TS cases and 4964 ancestry matched controls. The second component includes genome-wide association study (GWAS) data on 2106 TS cases from the second TS GWAS of 2716 TS cases and 3762 ancestry matched controls. The third component consists of 438 individuals representing 146 probands with DSM-IV-TR diagnosed Tourette Syndrome and their parents (146 complete parent-offspring trios). These individuals are part of the whole exome sequencing study, aiming to use whole exome sequencing of TS parent-offspring to identify de novo protein-truncating variants (PTVs) that are present in the child with TS but not in either parent. All subjects were collected by the Tourette Association of America International Consortium for Genetics (TAAICG) at seven sites in the United States and Canada. Both affected individuals and unaffected relatives were assessed for the presence of Tourette Syndrome and Chronic (Persistent) Tic Disorder (CTD) using a standardized, semi-structured interview, which has high clinical validity and reliability for the diagnoses of TS and CTD (TSAICG, Am J Hum Genet, 2007 (PMID: 17304708)); Darrow et al., Psychiatric Research, 2015 (PMID: 26054936)).

  Study phs001380

• Public Access Defibrillation Community Trial (PAD)(PAD-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives The Public Access Defibrillation (PAD) Community Trial sought to evaluate broad implementation of Public Access Defibrillators (PAD) in urban community units. Survival to hospital discharge of participants with out-of-hospital cardiac arrest was the main outcome measure. Survival was compared in community units (e.g., apartment or office buildings, gated communities, sports venues, senior centers, shopping malls) served by non-medical responders trained in CPR and use of automated external defibrillators (AEDs), to units receiving the traditional optimum community standard of care (i.e., rescuers trained to recognize a cardiac emergency, call 911, and initiate CPR). Background Sudden out-of-hospital cardiac arrest (OOH-CA) remains a significant cause of death, in spite of recent declines in overall mortality from cardiovascular disease. Existing methods of emergency resuscitation are inadequate due to time delays inherent in transporting trained responders with defibrillation capabilities to the side of the OOH-CA victim. Existing Emergency Medical Services (EMS) systems typically combine paramedic Emergency Medical Technician (EMT) services with some level of community involvement, such as bystander cardiopulmonary resuscitation (CPR) training. Some communities include automated external defibrillators (AEDs) at isolated sites or in mobile police or fire vehicles. Such an approach typically varies in effectiveness, with an incremental improvement in effectiveness seen in communities that organize and integrate services with the existing EMS system. However, optimal improvement in survival from sudden OOH-CA may require a program that utilizes volunteer non-medical responders (who may not have a traditional duty to respond to an emergency) trained to use AEDs. Participants The PAD trial was a prospective, randomized community based trial. More than 19,000 volunteer responders from 993 community units in 24 North American regions participated. The two study arms had similar unit and volunteer characteristics. Participants with treated out-of-hospital cardiac arrest in the two groups were similar in age (mean: 69.8 years), proportion of men (67 perecnt), rate of cardiac arrest in a public location (70 percent), and rate of witnessed cardiac arrest (72 percent). Conclusions Community units with volunteers trained in CPR and AEDs had significantly more participants surviving to hospital discharge than units with volunteers trained to use CPR only. There were 30 survivors among 128 definite cardiac arrests in the CPR+AED units and 15 survivors among 107 definite cardiac arrests in the CPR only units (p = 0.03). Serious adverse effects were rarely reported. No volunteers received inadvertent shocks, and no participants were shocked unnecessarily. AED maintenance problems were infrequent. A few participating volunteers reported severe stress related to responding to emergency situations. Although residential complexes represented 16% of the units and 29% of the treatable cardiac arrests, only 5% of the survivors were from residential complexes. Such information should be helpful for individual facilities that are considering implementing PAD programs. (NEJM 2004; 351:637-46).

  Study phs003858

• Efficacy of dual KRAS G12D–EGFR blockade versus triple combinations in patient-derived models of KRAS G12D-mutant colorectal cancer

  RNA sequencing was performed on patient-derived xenograft (PDX)-derived organoid models of metastatic colorectal cancer (mCRC). The aim of this study was to characterize the transcriptional landscape of KRAS-mutant mCRC cells in response to therapeutic strategies targeting the EGFR and KRAS signaling pathways. Transcriptomic profiling was conducted following drug treatments to investigate molecular changes associated with single and combination therapies. A total of 24 samples were analyzed.

  Study EGAS50000001700

• Transcriptomic analyses of a large cohort of adult B cell acute lyphoblastic leukemia

  Total mononuclear cells (MNC) were isolated from peripheral blood (PB) or bone marrow (BM) samples of 105 Ph-/-/- (B-cell acute lymphoblastic leukemia [B-ALL] triple negative) and 31 Ph+ B-ALL adult patients using Lymphosep (Biowest, Nuaillé, France). A total of 15 samples from healthy subjects were processed including hematopoietic stem-progenitor cells (CD34+) from bone marrow specimens (n = 3), and bone marrow mononuclear cell samples (n = 3) from STEMCELL Technologies (Vancouver, Canada). PB MNC samples (n=5) and cord blood samples (n = 4). CD34+ cells were enriched from cord blood samples by immunomagnetic separation (CD34 MicroBead Kit, Miltenyi Biotec, Bergisch Gladbach, Germany).Libraries were prepared using the TruSight RNA Pan-Cancer Panel Kit (Illumina, San Diego, California, USA), following the manufacturer’s protocol. Sequencing was performed using the Illumina MiSeq instrument.

  Dataset EGAD00001010837

• Rapid Acceleration of Diagnostics - Underserved Populations (RADx-UP): COVID-19 Testing and Vaccination Social Network Diffusion for Diverse Criminal Legal Involved Communities

  This RADx-UP Phase II proposal, "Social network diffusion of COVID-19 prevention for diverse Criminal Legal Involved Communities", will implement a situation appropriate COVID-19 testing and vaccination social network diffusion intervention - C3 - building upon RADx-UP Phase I lessons and successful social network prevention interventions developed previously by the research team. C3 Criminal Legal Involved (CLI) populations encompass those non-incarcerated who have experienced recent arrest, incarceration, probation, parole or diversion programs such as drug courts. While increases in COVID-19 testing have been observed among this group, there remain members with limited testing history as well as individuals who are vaccine hesitant. COVID-19 prevention messaging can no longer be simplified to "everyone test and/or everyone vaccinate" as testing and vaccination decisions among community members are sensitive to personal histories (i.e., prior infection), local infection rates (i.e., low rates) and testing/vaccination availability. As COVID-19 prevention efforts have become more complicated (i.e., test if exposed), people tend to focus on the messenger, and particularly those that are close to them. Personal connections and communications within existing personal network structures, such as families, friends and other trusted acquaintances represent the cornerstone to increase situation appropriate testing and overcoming COVID-19 vaccine hesitancy. C3 builds upon RADx-UP I, by using a network diffusion approach facilitated through motivational interviewing purposefully geared to mobilize one's own organic social network to increase context appropriate testing and vaccine uptake. Through this process we will maximize the primary benefit and impact of this type of intervention which also has the intended effect of increasing likelihood that the messenger themselves will undergo the same behavior change that they have been trained to promote. We will leverage infrastructure developed in RADx-UP Phase I, which includes 4 high-impact sites across the Central US from Phase I: Baton Rouge LA, Little Rock AR, Indianapolis IN, and Chicago IL. We will utilize established engagement efforts already in place and continue to fully integrate communities in the strategic application of the intervention. We will use the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework to guide implementation. C3 aims to: Aim 1a. Test the efficacy (3-month situation appropriate testing or vaccination) of a network diffusion intervention (C3) versus an existing COVID-19 testing and vaccine linkage to care intervention among: 1) primary study participants (primary outcome); and 2) secondary study participants connected to primary participants (secondary outcome) using a RCT design. Aim 1b. Explore the mechanisms for differential intervention effects at the individual and network-level that may increase situation appropriate testing and/or vaccination uptake. Aim 2. Examine key RE-AIM components in real time tied to the implementation of the network diffusion intervention (C3).

  Study phs003234

• Circulating tumor cells Exome sequencing from breast cancer

  Single cell technologies allow interrogating the extent of tumor heterogeneity, providing novel insights into tumor evolution and treatment resistance mechanisms. Here, we investigated the level of genetic heterogeneity among circulating tumor cells (CTCs) at the single nucleotide variation and copy number aberration (CNA) levels and compared it to synchronous matched primary tumor/metastatic lesion from 3 metastatic breast cancer patients with triple-negative (TNBC), HER2-positive (HER2+) and estrogen-receptor-positive (ER+) tumors. Whole exome sequencing was performed on 3 synchronous bulk tumor tissue and 21 single/pooled CTC samples. When comparing bulk tissue with CTCs from the same patient, we found similar CNA profiles and the same patient-specific driver mutations for the HER2+ and TNBC tumors. Different CNA profiles and driver mutations were found for the ER+ tumor, with two distinct clones being identified in the CTCs, one harboring an activating ESR1 mutation, the other one bearing a TP53 mutation. These data suggest that tumor tissue and CTCs provide in a subset of patients complementary clinically relevant information to map tumor heterogeneity and monitor tumor evolution. Further validation is needed.

  Study EGAS00001005228

• Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer

  Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma (HGSOC). Here we show that somatic copy number alterations (SCNAs) in frequently amplified HGSOC cancer genes significantly correlate with gene expression and methylation status. We identified five prevalent clonal driver SCNAs (chromosomal amplifications encompassing MYC, PIK3CA, CCNE1, KRAS and TERT) from multi-regional HGSOC data and reasoned that their strong selection should prioritise them as key biomarkers for targeted therapies. We used primary HGSOC spheroid models to test interactions between in vitro targeted therapy and SCNAs. MYC chromosomal copy number was associated with in-vitro and clinical response to paclitaxel and in-vitro response to mTORC1/2 inhibition. Activation of the mTOR survival pathway in the context of MYC-amplified HGSOC was statistically associated with increased prevalence of SCNAs in genes from the PI3K pathway. Co-occurrence of amplifications in MYC and genes from the PI3K pathway was independently observed in squamous lung cancer and triple negative breast cancer. These results suggest that identifying co-occurrence of clonal driver SCNA genes could be used to tailor therapeutics for precision medicine.

  Study EGAS00001006200

• Identification of improved IL28B SNPs and haplotypes for prediction of drug response in treatment of hepatitis C using massively parallel sequencing in a cross-sectional European cohort

  The hepatitis C virus infects nearly 3% of the World’s population, causing severe liver disease in many. Standard of care therapy is currently pegylated interferon alpha and ribavirin (PegIFN/R), which is effective in less than half of those infected with the most common viral genotype. Two IL28B SNPs, rs8099917 and rs12979860, predict response to (PegIFN/R) therapy in treatment of hepatitis C virus infection. These SNPs were identified in genome wide analyses using Illumina genotyping chips. In people of European ancestry, there are 6 common (>1%) haplotypes for IL28B, one tagged by rs8099917 minor allele, four tagged by rs12979860. We used massive parallel sequencing of the IL28B and IL28A gene regions generated by PCR from pooled DNA samples from 100 responders and 99 non-responders to therapy, to identify common variants. Variants that had high odds ratios and were validated were then genotyped in a cohort of 905 responders and non-responders. Their predictive power was assessed, alone and in combination with HLA-C. Only SNPs in the IL28B linkage disequilibrium block predicted drug response. Eighteen SNPs were identified with evidence for association with drug response, and with a high degree of confidence in the sequence call. We found that two SNPs, rs4803221 (homozygote minor allele positive predictive value (PPV) of 77%) and rs7248668 (PPV 78%), predicted failure to respond better than the current best, rs8099917 (PPV 73%) and rs12979860 (PPV 68%) in this cross-sectional cohort. The best SNPs tagged a single common haplotype, haplotype 2. Genotypes predicted lack of response better than alleles. However, combination of IL28B haplotype 2 carrier status with the HLA-C C2C2 genotype, which has previousl y been reported to improve prediction in combination with IL28B, provides the highest PPV (80%). The haplotypes present alternative putative transcription factor binding and methylation sites. Massive parallel sequencing allowed identification and comparison of the best common SNPs for identifying treatment failure in therapy for HCV SNPs tagging a single haplotype have the highest PPV, especially in combination with HLA-C. The functional basis for the association may be due to altered regulation of the gene. These approaches have utility in improving diagnostic testing and identifying causal haplotypes or SNPs.

  Study EGAS00001000096

• Immune induction strategies to enhance the sensitivity to PD-1 blockade in metastatic triple negative breast cancer: the TONIC-trial

  The response rate in metastatic triple negative breast cancer (TNBC) to PD-1 blockade is low, highlighting an urgent clinical need for strategies that render the TNBC tumor microenvironment (TME) more sensitive to PD-1 blockade. Immunomodulatory mechanisms have been proposed for both chemotherapy and irradiation, but it has not been established whether these therapies may improve efficacy of PD-1 blockade by favorably changing the TME. In the first stage of this adaptive, non-comparative phase II trial (TONIC-trial; NCT02499367), 67 patients with metastatic TNBC were randomized to nivolumab without induction or to one of four induction treatments, consisting of irradiation of one metastatic lesion (3x8 Gy) or a two- week low-dose regimen of cyclophosphamide, cisplatin or doxorubicin, all followed by nivolumab. In the overall cohort of 66 evaluable patients, the objective response rate (ORR; iRECIST16) was 20% (95% CI: 11%-31%), with two complete responses and 11 partial responses. The majority of clinical responses were observed on nivolumab in the cisplatin (ORR 23%; 3/13) and doxorubicin (ORR 35%; 6/17) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes, involved in PD-1/PD-L1, and T-cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK-STAT and TNFα-signaling after doxorubicin. In addition, we observed a trend towards increased T-cell infiltration, measured using T-cell receptor (TCR) sequencing, after doxorubicin. Together, the clinical and translational data of this study testing different immune induction strategies prior to nivolumab suggest that short-term doxorubicin and cisplatin may induce a more favorable TME and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant further confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types.

  Study EGAS00001003535

• INSPIRE multi-timepoint cfMeDIP dataset

  This dataset contains raw sequencing data from multi-timepoint cell-free methylated DNA immunoprecipitation and sequencing (cfMeDIP-seq) of plasma samples from the INSPIRE study (NCT02644369). Details about the study, including inclusion/exclusion criteria and interventions are available at https://clinicaltrials.gov/study/NCT02644369. Briefly, five cohorts were included, INS-A (head & neck squamous cell carcinoma), INS-B (triple-negative breast cancer), INS-C (high-grade serous ovarian cancer), INS-D (melanoma), and INS-E (mixed solid tumors). All patients in the study were diagnosed with advanced cancer and received treatment with pembrolizumab. Plasma samples were collected at baseline and every 3 cycles until disease progression, death, loss of follow-up, or completion of the study. Plasma samples were first processed for cell-free DNA mutations and remaining samples were then processed by cfMeDIP-seq, prioritizing baseline and post-cycle 3 samples. In total, data from 204 timepoints from 87 distinct patients are deposited.

  Dataset EGAD00001011312

• Characterizing Advanced Breast Cancer Heterogeneity and Treatment Resistance through Serial Biopsies and Comprehensive Analytics

  This dataset accompanies the manuscript "Characterizing Advanced Breast Cancer Heterogeneity and Treatment Resistance Through Serial Biopsies and Comprehensive Analytics". In this study we discuss the clinical implications and consequences of molecular heterogeneity in a metastatic breast cancer patient identified through serial biopsies, multi-omic analysis, and longitudinal patient monitoring, performed through the precision oncology program, Serial Measurements of Molecular and Architectural Responses to Therapy (SMMART). This case study describes a metastatic breast cancer patient with a highly heterogenous tumor that began as ER positive/HER2 negative on diagnosis, then was found to be ER negative/HER2 positive in a metastatic liver lesion (Study biopsy #1), and finally triple negative (TNBC) in another metastatic liver biopsy (Study biopsy #2). Multi-omic assays included clinical genomic panel sequencing, clinical immunohistochemistry, a clinical protein profiling assay (Intracellular Signaling Protein Profiling), RNA sequencing, and RPPA. Here we provide the expression data from RNAseq and RPPA data on Study biopsy #2 for the patient discussed in this case report. Note: The first liver biopsy did not yield sufficient material for RNAseq or RPPA.Raw RNA FASTQ files from Study biopsy #2 of the liver Gene expression (RNAseq) files from Study biopsy #2Protein expression (RPPA) files (level 2, 3, 4) for Study biopsy #2

  Study phs002321

• IDENTIFICATION AND TARGETED MANAGEMENT OF A PATIENT WITH A NEURODEGENERATIVE DISORDER CAUSED BY BIALLELIC MUTATIONS IN SLC5A6

  We describe a sibling pair displaying an early infantile-onset, progressive neurodegenerative phenotype, with symptoms of developmental delay and epileptic encephalopathy developing from 12 to 14 months of age. Using whole exome sequencing, compound heterozygous variants were identified in SLC5A6, which encodes the sodium-dependent multivitamin transporter (SMVT) protein. SMVT is an important transporter of the B-group vitamins biotin, pantothenate and lipoate. The protein is ubiquitously expressed and has major roles in vitamin uptake in the digestive system, as well as transport of these vitamins across the blood-brain barrier. Pathogenicity of the identified variants was demonstrated by impaired biotin uptake of mutant SMVT. Identification of this vitamin transporter as the genetic basis of this disorder guided targeted therapeutic intervention, resulting clinically in improvement of the patient’s neurocognitive and neuromotor function. This is the second report of biallelic mutations in SLC5A6 leading to a neurodegenerative disorder due to impaired biotin, pantothenate and lipoate uptake. The genetic and phenotypic overlap of these cases confirms mutations in SLC5A6 as the genetic cause of this disease phenotype. Recognition of the genetic disorder caused by SLC5A6 mutations is essential for early diagnosis and to facilitate timely intervention by triple vitamin (biotin, pantothenate and lipoate) replacement therapy.

  Study EGAS00001003861

• Gene signature for predicting homologous recombination deficiency in triple-negative breast cancer

  We developed a gene expression-based classifier for homologous recombination deficiency (HRD) in breast cancer patients using WES and RNA-seq data obtained from 94 TNBC samples from a Malaysian hospital-based cohort (MyBrCa). This classifier was able to predict for high levels of a mutational signature associated with HRD in an additional MyBrCa TNBC validation cohort (this EGA study) as well as in TNBCs from TCGA. We also validated the classifier on a NanoString platform with both fresh frozen and FFPE tissue.

  Study EGAS00001006518

• Comparison of single/pooled CTCs and bulk exome sequencing

  Single cell technologies allow the interrogation of tumor heterogeneity, providing insights into tumor evolution and treatment resistance. To better understand whether circulating tumor cells (CTCs) could complement metastatic biopsies for tumor genomic profiling, we characterized 11 single CTCs and 10 pooled CTC samples at the mutational and copy number aberration (CNA) levels, and compared these results with matched synchronous tumor biopsies from 3 metastatic breast cancer patients with triple-negative (TNBC), HER2-positive and estrogen receptor-positive (ER+) tumors. Similar CNA profiles and the same patient-specific driver mutations were found in bulk tissue and CTCs for the HER2-positive and TNBC tumors, whereas different CNA profiles and driver mutations were identified for the ER+ tumor, which presented two distinct clones in CTCs defined by mutations in ESR1 Y537N and TP53, respectively. Furthermore, de novo mutational signatures derived from CTCs described patient-specific biological processes. These data suggest that tumor tissue and CTCs provide complementary clinically relevant information to map tumor heterogeneity and tumor evolution.

  Dataset EGAD00001009052

• Aurora US Metastatic Breast Cancer Retrospective Project

  The AURORA US Metastatic Breast Cancer project is funded by the Breast Cancer Research Foundation (BCRF) Evelyn H. Lauder Founder's Fund for Metastatic Breast Cancer Research. This multi-center effort conducted within the Translational Breast Cancer Research Consortium (TBCRC) and cancer researchers to better understand the metastatic process through the study of both the primary and metastatic tissue. In the retrospective phase, TBCRC sites submitted matched primary and metastatic tissues and blood from previous collections for piloting the process. Samples were profiled using whole genome DNA sequencing, whole exome DNA sequencing, DNA methylation arrays, and RNA sequencing. The final freeze set for samples with successful nucleic acid extraction and molecular assays included 55 patients with 31 primary tissues and 102 metastases. Twenty patients had tissue collected at autopsy and included 19 with more than one metastasis. Metastases were from 20 different tissue locations with the most common sites being liver, lung, lymph node, and brain. The median age at primary diagnosis was 49 years. The clinical subtypes of the primary tumors were 34% Triple Negative, 30% ER+HER2-, 11% ER+HER2+, and 7% ER-HER2+. Patients received an average of 3 lines of therapy in the metastatic setting. The median overall survival from primary diagnosis was 4.5 years and overall survival from metastatic diagnosis was 2 years.

  Study phs002622

• Integrated Metabolic Profiling and Gene Expression Analysis Reveals Therapeutic Modalities in Breast Cancer

  In this study, we performed metabolite profiling and RNA-sequencing on human breast cancer tumors and normal breast tissue samples, including triple negative breast cancer (TNBC), estrogen receptor positive breast cancer (ER+) and paired normal samples, and patient-derived xenografts (PDX) samples. Here, we report two distinctive groups defined by metabolites; a TNBC-HIGH group that shows high levels of pyrimidine pathway metabolites and biosynthetic enzymes, and an ER-HIGH group that shows high levels of fatty acid and arginine biosynthesis intermediates. We identify different metabolic enrichment profiles between cell lines grown in vitro vs. in vivo; cell lines grown in vivo recapitulate patient tumors metabolic profiles. Further, we identify a subset of genes that strongly correlates with the TNBC-HIGH metabolic profile using integrated metabolic and gene expression profiling, which strongly predicts patient prognosis when tested on larger human datasets. As a proof-of-principle, when we target TNBC-HIGH metabolic dysregulation with a pyrimidine biosynthesis inhibitor (Brequinar), and/or a glutaminase inhibitor (CB-839), we observe therapeutic efficacy and decreased tumor growth in representative TNBC cell lines, murine p53-null mammary tumors, and in vivo patient-derived xenografts (PDXs) upon multi-agent drug treatment. This study highlights potential new therapeutic opportunities in breast cancers guided by a genomic biomarker, which could prove impactful for breast cancers that rapidly proliferate.

  Study phs002396

• PAX5 biallelic genomic alterations define a novel subgroup of B cell precursor acute lymphoblastic leukemia

  Chromosomal rearrangements and specific aneuploidy patterns are initiating events and define subgroups in B cell precursor acute lymphoblastic leukemia (BCP-ALL). Here we analyzed 250 BCP-ALL cases and identified a novel subgroup (‘PAX5-plus’, n=19) by distinct DNA methylation and gene expression profiles. All patients in this subgroup harbored mutations in the B-lineage transcription factor PAX5, with p.P80R as hotspot. Mutations either affected two independent codons, consistent with compound heterozygosity, or suffered LOH predominantly through chromosome 9p aberrations. These biallelic events resulted in disruption of PAX5 transcriptional programs regulating B cell differentiation and tumor suppressor functions. Homozygous CDKN2A/B deletions and RAS activating hotspot mutations were highly enriched as cooperating events in the genomic profile of PAX5-plus ALL. Together this defined a specific pattern of triple alterations, exclusive to the novel subgroup. PAX5-plus ALL was observed in pediatric and adult patients. Although restricted by the limited sample size, a tendency for more favorable clinical outcome was observed with 10 of 12 adult PAX5-plus patients achieving long-term survival. PAX5-plus represents the first BCP-ALL subgroup defined by sequence alterations in contrast to gross chromosomal events and exemplifies how deregulated differentiation (PAX5), impaired cell cycle control (CDKN2A/B) together with sustained proliferative signaling (RAS) cooperatively drives leukemogenesis.

  Study EGAS00001003209

• Mutational dynamics of triple negative breast cancer over neoadjuvant chemotherapy treatment reveal frequent whole genome duplication events

  Background Triple-negative breast cancer (TNBC) is associated with poor survival rate and high genomic instability, generating complex tumour genomes. However, the processes generating this complexity are poorly studied over time. Here, we study the temporal dynamics of TNBC somatic mutations, revealing major transitions in tumour genome evolution, from diagnostic biopsies, through treatment, to cancer remission or recurrence. Methods Deep whole exome sequencing and CUTseq, a reduced representation whole genome sequencing approach, were performed in parallel, to comprehensively identify short nucleotide variants (SNVs), copy number alterations (CNAs) and aneuploidies genome-wide. We profiled (N=74) tumour samples from 22 patients across the course of disease, including spatially diverse samples from many tumours, allowing us to observe the gain and loss of candidate driver variants over time. Results As expected, tumour infiltrating lymphocyte (TIL) levels and residual cancer burden (RCB) score were negatively correlated, with good responses to neoadjuvant chemotherapy (NACT) seen in pre-treatment samples with high infiltration. In general, SNV mutational burden remained stable across disease progression and RCB classes. Recurrent SNVs across the cohort implicated several known TNBC driver genes in disease progression and response to treatment, with TP53, MICA, CYP2D6, BRCA1 and BRCA2 frequently altered. However, the presence of candidate driver SNVs in these genes often varied throughout a patient’s treatment, including the loss of those seen in a given driver gene in pre-treatment samples, but gain of novel variants in the same gene at later time points. Dramatic structural dynamics were seen in all tumours, including abundant CNA including chromosome arm aneuploidies seen in pre-treatment samples, followed by frequent loss of these alterations post-treatment, and their re-emergence at recurrence. Whole genome duplication (WGD) events appear to drive these dynamics, with a higher frequency of pre-treatment WGD seen in patients with the best response to NACT. Conclusions Comprehensive longitudinal profiling demonstrates the complex interplay of SNVs and copy number alterations during TNBC progression, leading to diverse evolutionary trajectories and patient outcomes. Complex mutational patterns emerge as important features during progression, with WGD events emerging as potential candidate biomarkers of response at both tumour establishment and recurrence.

  Study EGAS00001008261

• Integration of genomics and histology reveals diagnosis and effective therapy of refractory cancer of unknown primary with PDL1 amplification (H021)

  Identification of the tissue of origin in cancer of unknown primary (CUP) poses a diagnostic challenge and is critical for directing site-specific therapy. Currently, clinical decision making in patients with CUP primarily relies on histopathology and clinical features. Comprehensive molecular profiling has the potential to contribute to diagnostic categorization and, most importantly, guide CUP therapy through identification of actionable lesions. We here report the case of an advanced-stage malignancy initially mimicking poorly differentiated soft-tissue sarcoma that did not respond to multi-agent chemotherapy. Molecular profiling within a clinical whole-exome and transcriptome sequencing program revealed a heterozygous, highly amplified KRAS G12S mutation, compound-heterozygous TP53 mutation/deletion, high mutational load, and focal amplification of chromosomes 9p (including PDL1 [CD274] and JAK2) and 10p (including GATA3). Integrated analysis of molecular data and conventional histopathology suggested a diagnosis of triple-negative breast cancer (TNBC) and provided a rationale for immune checkpoint inhibitor therapy with pembrolizumab, which resulted in rapid clinical improvement and a lasting partial remission. Analysis of 157 TNBC samples from The Cancer Genome Atlas revealed focal, high-level PDL1 amplification coinciding with excessive PDL1 mRNA expression in 24% of cases. Collectively, these results illustrate the diagnostic utility of multidimensional tumor profiling in cases with non-descript histology and immune phenotype, demonstrate the predictive power of genomic PDL1 amplification for immune checkpoint inhibition, and suggest a targeted therapeutic strategy in chromosome 9p24.1/PDL1-amplified cancers.H021

  Study EGAS00001001846

• WGS of TNBC PDXs

  WGS data relative to 36 triple negative breast cancer PDX models.

  Dataset EGAD00001008535

• Sporadic ALS Australia Systems Genomics Consortium (SALSA-SGC)

  In 2016 we established the Sporadic ALS Australia Systems Genomics Consortium (SALSA-SGC) funded by the Ice Bucket Challenge Grant administered by the Motor Neurone Disease Research Institute of Australia. The goals of the SALSA-SGC are to collect biological samples from clinics across Australia with matched in depth clinical and self-report phenotypes and to generate multiple levels of genetic and genomic data. In this first data generation exercise of the SALSA-SGC the majority of the samples were collected prior to the formal establishment of SALSA-SGC from clinics across Australia.Briefly, the cohort includes the University of Sydney’s Australian Motor Neuron Disease DNA Bank (MND Bank) cohort recruited April 2000 to June 2011), with study protocol approved by the Sydney South West Area Health Service Human Research Ethics Committee (HREC). Cases were recruited from around Australia via state-based MND associations with diagnosis verified by a neurologist. The remainder of the cases were recruited from clinics across Australia between 2015 and 2017 under HREC approvals from Royal Brisbane and Women’s Hospital, Macquarie University Multidisciplinary Motor Neurone Disease Clinic,  Calvary Health Care Bethlehem in Melbourne , Fiona Stanley Hospital in Perth, and from 2016 under HREC approvals at each site for the sporadic ALS Australia Systems Genomics Consortium (SALSA-SGC). The ALS cases were diagnosed with definite or probable ALS according to the revised El Escorial criteria. Some controls were recruited as either partners or friends of patients, healthy individuals free of neuromuscular diseases. We are providing GWAS and MWAS data in this dataset. Individual level GWAS data were generated using Illumina Infinium CoreExome-24 version 1.1 chips for N= 846 cases and N=665 controls. Individual MWAS data was generated using the Illumina Human methylation 450K array for N=782 cases and N=613 controls. There 1315 individuals where GWAS and MWAS data has been generated and is available. Further information on these data sets can be found: Paper 1: Restuadi, R, Garton, FC, Benyamin, B, Lin, T, et al. Amyotrophic Lateral Sclerosis Genetic Correlation with Cognitive Performance, educational attainment and schizophrenia: evidence from polygenic risk score analysis. (submitted) Paper 2: Nabais, MF, Lin, T, Benyamin, B et al. Significant out-of-sample classification from methylation profile scoring for amyotrophic lateral sclerosis. 2020. NPJ genomic medicine. 5(10). Files provided in this submission include: GWAS: This folder contains QCed genotype for the Australian ALS case-control cohort. Contains PLINK files for genotyping data (not imputed yet). The individuals selected here have: good consistency on phenotype data ethics approval registered as part of sporadic ALS studies unrelated by GRM cut-off 0.05 No ancestry QC yet MWAS: This folder contains the IDAT and post-QC normalized DNAm (beta) for the Australian ALS case-control cohort. 2019_AUS_ALS_PCTG_DNAm.tar.gz - IDATS for 1315 individuals analyzed in the MWAS study normalized_beta_values - Binary files (created with the OSCA software) containing information on the individuals, probes and the DNAm (beta) values obtained after QC phenotype_file - contains all the covariates analysed in the MWAS including: case-control status, coded 0 = Control and 1 = ALS, predicted age, predicted cell-type proportions, predicted smoking scores, slide and chip position and sex Important Notes: The DNAm data were normalized together with samples that were not part of this ALS case/control study and thus, the normalization procedure may not be 100% reproducible using only the IDAT files uploaded here. Summary data has been made publicly available and can be accessed directly: Data collection and sample processing were performed at several clinics across Australia. Genotyping and DNA methylation arrays were performed by the Human Studies Unit, at the Institute for Molecular Bioscience (University of Queensland). Quality control of the genotypic, phenotypic and DNA methylation data was done by the Program of Complex Traits Genomics, at the Institute for Molecular Bioscience (University of Queensland).

  Study phs002068

• Projects

  Projects Jointly managed by the European Bioinformatics Institute (EMBL-EBI) in Cambridge (UK) and the Centre for Genomic Regulation (CRG) in Barcelona, the EGA provides an invaluable service to the worldwide biomedical research community. The teams leading the EGA are involved in several international partnerships and consortia in numerous scientific fields, where they contribute to ambitious projects. In addition to the project listed below, The EGA is in a long-standing partnership with the Global Alliance for Genomics and Health (GA4GH), as described on the dedicated page. On-going projects Project Duration Domain Funder Tags EASIGEN-DS | The EASIGEN-DS project aims to conduct a design study to establish a new European Research Infrastructure on Advanced Genomics Technologies, EASIGEN. To develop an excellent scientific, technological and operational design, we will conduct landscape studies, stakeholder consultations, and community surveying. 2025-2028 Genomic and health data Horizon Europe DATA MANAGEMENT DOCUMENTATION INFRASTRUCTURE Go-IMPaCT | Go-IMPaCT will contribute sequenced genomes and provide infrastructure as part of IMPaCT-Cohort, one of the three fundamental pillars of the Precision Medicine Infrastructure associated with Science and Technology (IMPaCT) program in Spain. Along with the Genome of Europe (GoE) project, around 18.000 people will have their genomes sequenced, also contributing to Spain's commitments in 1+MG. Go-IMPaCT will fund the development of an EGA node to manage and share this genomic and phenoclinic data, laying the foundations for regional and ethnic genomic variability in Spain to be available for research purposes. The IMPaCT cohort is created with the spirit of being an open research tool, compatible with the rest of the health research ecosystem, and other international initiatives. 2025-2027 Large-scale genomics and health data; personalised medicine Instituto de Salud Carlos III ACCESS DISCOVERY INFRASTRUCTURE METADATA STANDARDS FAIR-FEGA | This project seeks to accelerate data depositions into FEGA, significantly increasing the data flow in and from FEGA nodes. It will build capacity within the FEGA nodes and increase awareness in a wide range of stakeholders, thus altogether achieving the ultimate goal of enhancing data reuse. The project will be carried out by a strategic consortium comprising seven ELIXIR nodes and two ELIXIR communities. 2025-2026 Not applicable ELIXIR ACCESS DISCOVERY DOCUMENTATION INFRASTRUCTURE METADATA STANDARDS FEGA-Connect | A consortium of six ELIXIR nodes plus the Polish FEGA node (in-kind contribution) joining forces to build a solid base to develop solutions for effective multi-omic sensitive data integration between FEGA nodes and other infrastructures and specialised Data repositories. We aim to promote a more coherent data deposition, discoverability and retrieval of multi-omics datasets, providing FAIRer data and consequently accelerating research. 2025-2026 Multi-omics data ELIXIR ACCESS DATA MANAGEMENT DISCOVERY INFRASTRUCTURE METADATA STANDARDS IMPaCT-Data 2 | IMPaCT-Data 2 will develop a digital platform for the integration and modelling of biomedical data associated with IMPaCT (Precision Medicine Infrastructure associated with Science and Technology) projects in Spain. It will deploy a sustainable infrastructure that facilitates the integration, standardisation, interoperability and analysis of clinical, genomic, molecular and medical imaging data. This platform will be aligned with European projects such as Genome of Europe (GoE), the first project to make use of the European Genomic Data Infrastructure (GDI), and EUCAIM. IMPaCT-Data 2 will benefit from advanced Artificial Intelligence and High Computing Capacity Systems capabilities, offering robust and accessible tools for researchers from the National Health System in Spain. 2025-2026 Large-scale genomics and health data; personalised medicine Instituto de Salud Carlos III ACCESS DISCOVERY INFRASTRUCTURE METADATA STANDARDS ERDERA | The European Rare Disease Research Alliance (ERDERA) takes over EJPRD to deliver concrete health benefits to rare disease patients in the next decade by advancing prevention, diagnosis and treatment research. To leave no one behind, over 170 organisations championed by the European Union and member states are working hand in hand to make Europe a world leader in rare diseases research and innovation. 2024-2034 Rare diseases Horizon Europe; "La Caixa" Foundation cofunds CRG's contribution ACCESS DATA ANALYSIS DISCOVERY INFRASTRUCTURE GoE | The Genome of Europe initiative aims to build a European network of national genomic reference cohorts of at least 500.000 citizens. These reference cohorts will be selected to be representative of the European population. 2024-2028 Large-scale genomic and health data Horizon Europe ACCESS DISCOVERY INFRASTRUCTURE METADATA STANDARDS HEREDITARY | HEREDITARY aims to transform the way we approach disease detection, prepare treatment response, and explore medical knowledge by building a robust, interoperable, trustworthy, and secure framework that integrates multimodal health data (including genetic data) while ensuring compliance with cross-national privacy-preserving policies. 2024-2027 Neurodegenerative disorders, gut-brain interplay Horizon Europe DATA MANAGEMENT DATA ANALYSIS EOSC-ENTRUST | The mission of EOSC-ENTRUST is to create a European network of trusted research environments for sensitive data and to drive European interoperability by joint development of a common blueprint for federated data access and analysis. 2024-2026 Trusted Research Environment Horizon Europe INFRASTRUCTURE EBV-MS | "Targeting Epstein-Barr Virus Infection for Treatment and Prevention of Multiple Sclerosis". The ambitious goals of the project are to answer the questions why only a few EBV infected persons develop MS, and define the underlying mechanism of this process, as well as clarify if targeting the EBV infection can prevent MS or improve the disease course. 2023-2028 Viral-host genetics; immune response; disease modelling; Disease prevention Horizon Europe DATA MANAGEMENT DATA ANALYSIS WISDOM | WELL-BEING IMPROVEMENT THROUGH THE INTEGRATION OF HEALTHCARE AND RESEARCH DATA AND MODELS WITHOUT BORDER FOR CHRONIC IMMUNE-MEDIATED DISEASES aims to deploy novel approaches for data processing, harmonisation, management, and secure data sharing and federated access for diseases like multiple sclerosis. Using an end-user guided approach, it will facilitate responsible and critical assessment of the use of AI in healthcare. 2023-2028 Chronic immune-mediated diseases Horizon Europe DATA MANAGEMENT INFRASTRUCTURE EUCAIM | EUropean Federation for CAncer IMages is a project that will build a highly secure, federated and large-scale European cancer imaging platform, with capabilities that will greatly enhance the potential of Artificial Intelligence in oncology. 2023-2027 Cancer Digital Europe Programme (DIGITAL) DISCOVERY CONTAGIO | CONTAGIO (COhorts Network To be Activated Globally In Outbreaks) aims to create coordination mechanisms to rapidly react to infectious disease (re-)emergence in low- and middle-income countries (LMICs). 2023-2026 Infectious Diseases European Commission - Horizon Europe ACCESS DATA MANAGEMENT DISCOVERY Youth-GEMs | Youth-GEMS (Gene Environment Interactions in Mental Health TrajectorieS of Youth) will conduct research into the genetic and environmental factors of mental health in young European people. 2022-2027 Mental health European Commission - Horizon Europe DATA MANAGEMENT DISCOVERY GDI | The European Genomics Data Infrastructure project is enabling access to genomic and related phenotypic and clinical data across Europe. It is doing this by establishing a federated, sustainable and secure infrastructure to access the data. 2022-2026 Genomic and health data European Commission - Horizon Europe; "La Caixa" Foundation cofunds CRG's contribution DISCOVERY DOCUMENTATION INFRASTRUCTURE EOSC4Cancer | EOSC4Cancer builds on existing projects, research outcomes and established community solutions to create the federated FAIR data, analysis and services infrastructure needed for European Cancer research programmes. 2022-2025 Cancer European Commission - Horizon Europe DISCOVERY IMPaCT-T2D | The IMPaCT-T2D project aims at studying the complete genomes of a large cohort of patients with Type 2 Diabetes mellitus (T2D), using modern sequencing technologies and artificial intelligence (AI) in order to improve the stratification and pharmacological treatment in the context of precision medicine. 2022-2025 Cardiovascular and Complex Diseases Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III ACCESS DATA MANAGEMENT DISCOVERY INFRASTRUCTURE EuCanImage | A European Cancer Image Platform Linked to Biological and Health Data for Next-Generation Artificial Intelligence and Precision Medicine in Oncology. 2020-2025 AI Solutions in Oncology European Commission - H2020 Programme; "La Caixa" Foundation cofunds CRG's contribution DATA MANAGEMENT METADATA STANDARDS GenoMed4ALL | A consortium built to empower personalised medicine in the field of haematological diseases through the use of AI and the pooling of genomic and clinical data. 2020-2025 Hematological diseases European Commission - H2020 Programme DISCOVERY METADATA STANDARDS Completed projects Project Duration Domain Funder Tags BY-COVID | The BeYond-COVID project aims to make COVID-19 data accessible to scientists in laboratories but also to anyone who can use it, such as medical staff in hospitals or government officials. Going beyond SARS-CoV-2 data, the project will provide a framework for making data from other infectious diseases open and accessible to everyone. 2021-2024 Infectious diseases European Commission - H2020 Programme ACCESS DATA MANAGEMENT DISCOVERY INFRASTRUCTURE IMPaCT-Data | IMPaCT-Data aims to create the infrastructure for secondary use of data from Spanish healthcare systems - electronic health records, medical imaging and genomic repositories - and contribute with the knowledge and methodology produced to the healthcare system. 2021-2024 Large-scale genomics and health dataSpanish Ministry of Science and Innovation; Instituto de Salud Carlos III ACCESS DATA MANAGEMENT DISCOVERY INFRASTRUCTURE LaMarató | It is a project aimed at creating and developing a catalan interhospitalary network to interrogate genetic variants from thousands of genetic tests carried out in patients with rare diseases from the main catalan hospitals. 2021-2024 Genomic and health data Fundació La Marató de TV3 (catalan foundation) DISCOVERY HealthyCloud | This consortium will contribute a Strategic Agenda towards the European Health Research and Innovation Cloud. The project will work in collaboration with a broad range of stakeholders to ensure that all voices are included and that the results are technically and ethically sound. 2021-2023 Not Applicable European Commission - H2020 Programme DOCUMENTATION B1MG | Beyond 1 Million Genomes aims to create a network of genetic and clinical data across Europe. The project provides coordination and support to the 1+ Million Genomes Initiative (1+MG). This initiative is a commitment of 24 EU countries, the UK and Norway to give cross-border access to one million sequenced genomes by 2022. 2020-2023 Not applicable European Commission - Horizon Europe DATA MANAGEMENT INFRASTRUCTURE METADATA STANDARDS ELIXIR-CONVERGE | An alliance with the goal of Connecting and aligning ELIXIR Nodes to deliver sustainable FAIR life-science data management services. 2020-2023 Data Management and Infectious Diseases European Commission - H2020 Programme DATA MANAGEMENT INFRASTRUCTURE METADATA STANDARDS IHCC | The International HundredK+ Cohorts Consortium aims to create a global platform for translational research – informing the biological and genetic basis for disease and improving clinical care and population health. 2020-2022 Translational research NIH; The Wellcome Trust; CZI INFRASTRUCTURE METADATA STANDARDS PPCG | The Pan Prostate Cancer Group aims to harmonise and interrogate Whole Genome DNA Sequence data generated around the world from over 2000 men with prostate cancer, with associated transcriptome and methylome data to include men from different clinical categories, and ethnicities. This project is about providing breakthrough advances through analysis of a very large series of Whole Genome DNA data from prostate cancer contributed by many of the leading scientists and clinicians working in prostate cancer genomics. 2019-2024 Cancer Cancer Research UK DATA MANAGEMENT CINECA | Consortium providing a Federated solution enabling population-scale genomic and biomolecular data accessible across international borders accelerating research and improving the health of individuals resident across continents. 2019-2023 Large-scale Genomics and Health Data European Commission - H2020 Programme ACCESS DATA MANAGEMENT DISCOVERY INFRASTRUCTURE EASI-Genomics | A project designed to provide easy access to cutting-edge DNA sequencing technologies to researchers from academia and industry, within a framework that ensures compliance with ethical and legal requirements, as well as FAIR and secure data management. 2019-2023 Next Generation Sequencing European Commission - H2020 Programme ACCESS EJP-RD | An European consortium built to create a comprehensive, sustainable ecosystem allowing a virtuous circle between research, care, and medical innovation. 2019-2023 Rare diseases European Commission - H2020 Programme ACCESS DATA MANAGEMENT DOCUMENTATION METADATA STANDARDS EOSC-Life | EOSC-Life brings together the 13 Life Science research infrastructures (LS RIs) to create an open, digital and collaborative space for biological and medical research. The project will publish 'FAIR' data and a catalogue of services provided by participating RIs for the management, storage and reuse of data in the European Open Science Cloud (EOSC). 2019-2023 Not applicable European Commission - H2020 Programme DOCUMENTATION EUCANCan | A federated network aiming at implementing a cultural, technological and legal integrated framework across Europe and Canada, to enable and facilitate the efficient sharing of cancer genomic data. 2019-2023 Cancer European Commission - H2020 Programme DATA MANAGEMENT METADATA STANDARDS The Federated EGA framework: supporting sensitive data management across the ELIXIR Nodes | This project is a direct continuation of the FHD IS with the goal to position the FEGA framework as the core infrastructure driver to support human data sharing for research. 2019-2023 Human genomic data ELIXIR INFRASTRUCTURE UK Biobank | UK Biobank is a large-scale biomedical database and research resource, containing in-depth genetic and health information from half a million UK participants. This project is to archive whole genome sequencing and other genetic data for UK Biobank participants. 2019-2023 Large-scale Genomics and Health Data The Wellcome Trust; UKRI; Amgen; AstraZeneca; GSK; Johnson & Johnson DATA MANAGEMENT INFRASTRUCTURE VEIS | The core mission of VEIS is to create an open ecosystem of technologies that will address and adapt to the requirements of the systems used to analyse and interpret -omics and clinical data in research and application environments in biomedicine. The aim of the project is to leverage the value of the EGA for both industry and society. 2019-2022 Oncology and Rare diseases Generalitat de Catalunya and European Regional Development Fund (ERDF) ACCESS DISCOVERY ELIXIR BEACON IS | This study follows on from a number of earlier activities that have established the ELIXIR Beacon Project. The main aim is to extend the Beacon protocol, developed at EGA, to become the reference ELIXIR Data Discovery product 2019-2021 Not applicable ELIXIR DISCOVERY ELIXIR FHD IS | This project coordinates the delivery of FAIR compliant metadata standards, interfaces, and reference implementation to support the federated ELIXIR network of human data resources. 2019-2021 Human genomic data ELIXIR INFRASTRUCTURE ELIXIR Rare Disease | The Rare Disease Community extends and generalises the system of access authorisation and high volume secure data transfer developed within the EGA. The goal of the Community is to create a federated infrastructure that will enable researchers to discover, access and analyse different rare disease repositories across Europe. It is doing this in partnership with other European infrastructure projects, namely RD-CONNECT, BBMRI-ERIC and E-Rare.2019-2021 Rare diseases ELIXIR INFRASTRUCTURE Solve-RD | Solve-RD - solving the unsolved rare diseases - is a research project funded by the European Commission. It echoes the ambitious goals set out by the International Rare Diseases Research Consortium (IRDiRC) to deliver diagnostic tests for most rare diseases by 2020. The current diagnostic and subsequent therapeutic management of rare diseases is still highly unsatisfactory for a large proportion of rare disease patients - the unsolved RD cases. For these unsolved rare diseases, we are unable to explain the etiology responsible for the disease phenotype, predict the individual disease risk and/or rate of disease progression, and/or quantitate the risk of relatives to develop the same disorder. 2018-2024 Rare diseases European Commission - H2020 Programme ACCESS DATA MANAGEMENT METADATA STANDARDS EuCanShare | An EU-Canada joint infrastructure for next-generation multi-Study Heart research. 2018-2022 Cardiovascular Diseases European Commission - H2020 Programme ACCESS METADATA STANDARDS

  Documentation about/projects-and-funders/projects

• A novel breast cancer cell line derived from a metastatic bone lesion of a breast cancer patient

  Purpose: We sought to generate and characterize a novel cell line from a breast cancer bone metastasis in order to better study the progression of the disease.Methods: The cell line, P7731, was derived from a metastatic bone lesion of a breast cancer patient and assessed for marker expression. P7731 was analyzed for DNA copy number variation, somatic mutations and gene expression and compared to the primary tumor. Results: P7731 cells are negative for estrogen receptor alpha (ERα), progesterone receptor (PR) and HER2 (triple-negative), strongly express vimentin (100% of cells positive) and also express cytokeratins 8/18 and 19 but at lower frequencies. Flow cytometry indicates P7731 cells are predominantly CD44+/CD49f+/EpCAM-, consistent with a primitive, mesenchymal-like phenotype. The cell line is tumorigenic in immunocompromised mice. Exome sequencing identified a total of 45 and 76 somatic mutations in the primary tumor and cell line respectively, of which 32 were identified in both samples and included mutations in known driver genes PIK3CA, TP53 and ARID1A. P7731 retains the DNA copy number alterations present in the matching primary tumor. Homozygous deletions detected in the cell line and in the primary tumor were found in regions containing three known (CDKN2A, CDKN2B and CDKN1B) and 23 putative tumor suppressor genes. Cell line specific gene amplification coupled with mRNA expression analysis revealed genes and pathways with potential pro-metastatic functions.Conclusion: This novel human breast cancer-bone metastasis cell line will be a useful model to study aspects of breast cancer biology, particularly metastasis-related changes from breast to bone.

  Study EGAS00001002840

• Clonal fitness inferred from timeseries modeling of single cell cancer genomes

  Progress in defining genomic fitness landscapes in cancer by copy number alterations (CNA) has been impeded by lack of single cell and timeseries sampling. We generated 42,000 single cell whole genomes (scWGS) from breast epithelium and primary triple negative breast cancer (TNBC) patient-derived xenografts (PDX) collected during multi-year time series. Using a Wright-Fisher population genetics model, we inferred reproducible CNA-defined clonal fitness dynamics induced by TP53 mutation and cisplatin chemotherapy, with accurate forecasting of experimentally enforced clonal competition dynamics. Drug treatment in three long-term serially passaged TNBC PDX resulted in cisplatin resistant clones that had shown low fitness in the untreated setting. By contrast high fitness clones from treatment naive controls were eradicated reflecting an inversion of the fitness landscape. Upon drug release selective pressure dynamics were reversed indicating a fitness cost of treatment resistance. Taken together, our findings reveal clonal fitness dynamics linked to CNA and therapeutic resistance in polyclonal tumours.

  Study EGAS00001004448

• PD-L1 blockade in combination with carboplatin as immune induction in metastatic lobular breast cancer: the GELATO-trial

  Invasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype but published data on trials specific for ILC are so far lacking. Translational research revealed that a subset of ILCs may be immune-related and more sensitive to DNA-damaging agents such as platinum. In murine ILC models, synergy between immune checkpoint blockade and platinum has been observed. Here, we tested this concept in the phase II, GELATO-trial (NCT03147040), in which patients with metastatic ILC were treated with weekly carboplatin (AUC 1.5) as immune induction treatment for 12 weeks and atezolizumab (PD-L1 blockade; every three weeks) from the third week onwards until disease progression. Four out of 23 evaluable patients had a partial response (17%, 95%CI 5-39%) and two patients had stable disease for at least 24 weeks, resulting in a clinical benefit rate of 26% (95%CI 10-48%). Out of these six patients, four patients had triple-negative ILC (TN-ILC). In serial biopsies of metastatic lesions, we observed higher CD8 T-cell infiltration, expression of immune checkpoints, and exhausted T cells upon carboplatin/PD-L1 blockade. This is the first report of a clinical trial specifically for ILC and we demonstrate promising anti-tumor activity of atezolizumab with carboplatin as immune induction, in particular for TN-ILC. While activity of carboplatin/PD-L1 blockade in classical ER+ ILC was limited, our translational data yield important insights for the design of highly needed clinical trials in ILC.

  Study EGAS00001006902

• Breast Cancer in Blacks: Impact of Genomics, Healthcare Use and Lifestyle on Outcomes (BRIGHT)

  Young Black females bear a disproportionate burden of breast cancer (BC) mortality compared to White females and are underrepresented in clinical studies. It remains critical to understand factors that contribute to the high mortality from BC among young Black females in order to improve outcomes. The higher BC mortality rate among young Black females with breast cancer is partially attributed to the disproportionately higher proportions who develop the aggressive triple-negative breast cancer (TNBC). In addition to biologic factors, timely access to care, and lifestyle factors contribute to this disparity. Consequently, we sought to evaluate the interplay between biologic and non-biologic contributors to BC outcomes (i.e., BC disease-free survival (DFS)), and to better characterize the highly aggressive TNBC among young Black females based on distinct molecular subtypes. Ultimately, it is critical to assess both biologic and non-biologic factors to fully understand and address existing health disparities in this population. Through prior and subsequent recruitment of a population-based study of young Black females diagnosed with invasive breast cancer spanning 2009-2016, we: 1) assessed the contribution of biologic and non-biologic factors on BC-DFS observed among young Black females with BC, and 2) investigated molecular features of the subgroup with TNBC. Through this study, consented participants were asked to provide a saliva sample from which DNA was extracted for germline analyses, including germline inherited cancer genetic testing and Infinium Expanded Multi-Ethnic Genotyping Array. Breast cancer tumor specimens were also collected, and tumor RNA was extracted from viable FFPE tumor samples. Tumor RNA analyses included gene expression profiling through NanoString PAM50.Data that will be available through dbGaP for this study include SNP array data and PAM50 data.

  Study phs003466

• T-cell receptor sequencing of tumor-infiltrating lymphocytes (TIL) in breast cancer

  The spatial distribution of tumor-infiltrating lymphocytes (TIL) predicts breast cancer outcome and response to systemic therapy, highlighting the importance of an intact tissue structure for characterizing patients’ tumors. Here, we present ST-FFPE, a spatial transcriptomics method for the analysis of formalin-fixed paraffin-embedded samples, which opens the possibility of interrogating widely available archival tissue. The method involves extraction, exome capture and sequencing of RNA from different tumor compartments microdissected by laser-capture, and can be used to study the cellular composition of various tumor environments. Focusing on triple-negative breast cancer (TNBC), we characterized T cells, B cells, dendritic cells, fibroblasts and endothelial cells in both stromal and intra-epithelial compartments. We found a highly variable spatial distribution of immune cell subsets among tumors. This analysis revealed that the immune repertoires of intra-epithelial T and B cells were consistently less diverse than those of stromal T and B cells. T-cell receptor (TCR) sequencing confirmed a reduced diversity and revealed higher clonality of intra-epithelial T cells relative to the corresponding stromal T cells. Analysis of the top ten dominant clonotypes in the two compartments showed a majority of shared but also some unique clonotypes both in stromal and intra-epithelial T cells. Hyperexpanded clonotypes were more abundant among intra-epithelial than stromal T cells. These findings validate the ST-FFPE method and suggest an accumulation of antigen-specific T cells within tumor core. Because ST-FFPE is readily applicable for analysis of previously collected tissue samples, it could be useful for rapid assessment of intratumoral cellular heterogeneity in multiple disease and treatment settings.

  Study EGAS00001007125

• Single-cell transcriptome of T-ALL P1

  In this study, we profiled single-cell transcriptome (10X genomics) of Patient-derived xenografts (PDX) T-ALL replase samples from P1 patient. Primary human T-ALL cells were recovered from cryopreserved bone marrow aspirates of patients enrolled in the ALL-BFM 2009 study. Patient-derived xenografts (PDX) were generated as previously described by intrafemoral injection of 1 Million viable primary ALL cells in NSG mice110 PDX-derived (P1)28 cells were frozen until processing. For scRNA-seq library preparation, cryopreserved cells were thawed rapidly at 37 ℃ and resuspended in 10 ml warm Roswell Park Memorial Institute (RPMI) medium with 100 μg/ml Dnase I. Cells were centrifuged for 5 mins at 300 g, and resuspended in ice-cold phosphate buffered saline (PBS) with 2% foetal bovine serum (FBS) and 5mM EDTA. Cells were stained on ice with anti-murine-CD45-PE (mCD45)(clone 30-F11; BioLegend; 1:20) in the dark for 30 mins. 1:100 DAPI was added and incubated in the dark for 5 mins before sorting. Triple negative cells (DAPI-mCD45-GFP-) were sorted (Fig. S27) using a BD FACSAria™ Fusion Cell Sorter into ice cold 0.03% bovine serum albumin (BSA) in PBS. All isolated cells were immediately used for scRNA-seq libraries, which were generated as per the standard 10x Genomics Chromium 3′ (v.3.1 Chemistry) protocol. Completed libraries were sequenced on a NextSeq5000 sequencer (HIGH-mode, 75 bp paired-end).

  Dataset EGAD00001008325

• Longitudinal Study of Fluoride and Other Factors Related to Dental Fluorosis, Dental Caries, and Bone Health

  This project is a combination of the Iowa Fluoride Study and the Iowa Bone Development Study from 1992 - 2019. The Iowa Fluoride Study (IFS) began in 1992 with recruitment of 1,882 mothers of newborns from eight Iowa hospital post-partum wards from March 1992 to February 1995. The focus of the IFS was to collect detailed fluoride, general dietary intake, and other data several times per year from age 6 weeks on and relate them to dental fluorosis and dental caries (cavities). Data collection occurred 3-5 times per year initially, and then twice per year after ~ age 4. Dental exams of the primary (baby) teeth were initiated at ~ age 5.The Iowa Bone Development Study (IBDS) grew out of the IFS in 1998 when we added a "normal bone development" focus, and soon after the age 5 dental exams, we began to collect genetic samples and accelerometry (motion sensor) data. All then-active parents of IFS-participating children were invited to have their child join the IBDS, and the majority agreed to do so. The majority of participating children received both ~ age 5 dental exams and bone densitometry assessments. The bone densitometry at age 5 was determined by dual-energy X-ray absorptiometry (DXA) of the hip, lumbar spine, and whole body.Dental exams for caries and fluorosis were performed again at age 8-9, along with DXA bone scans and accelerometry. DXA scans and accelerometry were performed again at ages 11 and 15 years, along with peripheral quantitative computed tomography (pQCT) scans of the distal tibia and radius, but no dental exams were performed.At ages 13 and 17, dental exams, DXA and pQCT scans, as well as accelerometry, were obtained.At age 19, no dental exams were conducted, but repeat DXA and pQCT scans and accelerometry were obtained, along with multi-slice detector CT (MDCT) of the distal tibia.At age 23, we conducted the final wave of exams, which included dental, DXA, pQCT, MDCT, and accelerometry assessments.In addition, parents were invited to participate once with DXA bone scans and to also provide limited questionnaire data about their own fluoride and dietary exposures and physical activity.Note: Please refer to the document Iowa Fluoride Study/Iowa Bone Development Study (IFS/IBDS) - dbGaP Data Tables: A User's Guide - Version 2.0 for a detailed reference manual on all of the clinical data submitted for this project.Note: No genetic data or specimens were submitted with this study. However, many of the child/parent participants in the study were genotyped. These genotyping data are linked to dbGaP Study Accession: phs000095 under Dr. Mary Marazita: "Dental Caries: Whole Genome Association and Gene X Environment Studies".<img style="width: 1155px;" 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

  Study phs002203

• Environmental Arsenic and Diabetes Mellitus (Chihuahua Cohort)

  The Chihuahua Cohort was established as part of a larger NIEHS-funded project that used laboratory models (tissue culture and mice) and human subjects to examine the association between exposure to arsenic and diabetes, including identification of mechanisms underlying this association. All procedures involving human subjects were approved by institutional review boards at the University of North Carolina at Chapel Hill and Cinvestav-IPN (Centro de Investigaci&#243;n y de Estudios Avanzados del Instituto Polit&#233;cnico Nacional, Mexico City, Mexico). All participants provided signed informed consent. A total of 1,160 adults (&#8805; 18 years old) with a minimum 5-year uninterrupted residency in the Chihuahua study area were recruited between 2008 and 2012. Samples of drinking water were obtained from the participants' households. Data on residency, occupation, drinking-water sources and use, smoking, alcohol consumption, and medical history were recorded by a study questionnaire. Spot urine and fasting venous blood were collected during medical examination that included an oral glucose tolerance test (OGTT) with blood drawn 2 hr after a 75-g glucose dose. Plasma from both fasting and 2-hr blood samples was collected. Body mass index (BMI) of each participant was calculated from body weight and height. BMI cutoffs of &#8805; 25.0, &#8805; 30, and &lt; 18.5 kg/m2 were used to define overweight, obese, and underweight individuals, respectively. Participants' waist circumference was also measured. Blood pressure was assessed using a manual sphygmomanometer. Three measurements were taken at intervals of at least 1 min, with a 5-min rest before obtaining the first reading; the mean of the last two measurements was used. The concentrations of arsenic in drinking water and arsenic species in urine were measured by hydride generation-atomic absorption spectrometry. The limit of detection for As in water as well as for As species in urine was 0.01 &#181;g As/L. Creatinine concentration in urine was determined using an established colorimetric assay. DNA was isolated from blood for genotyping analysis.The following measures were taken: glucose concentration in fasting blood (FBG) and in blood collected 2 hours into OGTT (2HBG); concentrations of triglycerides, HDL and total cholesterol (TC) in fasting plasma; and LDL was calculated using the Friedewald equation. Diabetes was classified by FPG &#8805; 126 mg/dL, 2HPG &#8805; 200 mg/dL, or self-reported diabetes diagnosis or medication use (WHO/International Diabetes Federation 2006). Prediabetes was defined as the absence of diabetes with FPG &#8805; 110 mg/ dL or 2HPG &#8805; 140 mg/dL. Elevated fasting levels of each lipid were defined as plasma TG &#8805; 150 mg/dL, TC &#8805; 200 mg/dL, and LDL &#8805; 130 mg/dL. Fasting HDL &lt; 40 mg/dL in men and &lt; 50 mg/dL in women were designated as low. Hypertension was defined by systolic blood pressure (SBP) &gt; 140 mm Hg, diastolic blood pressure (DBP) &gt; 90 mmHg, or self-reported use of anti-hypertensive medication. Genotyping analysis, which will be available in version 2 of this study, was carried out in a subset of ~600 subjects with focus on enzymes involved in the metabolism of arsenic, including AS3MT, GSTs.All data collected during the medical exams or generated by the above-described chemical and biochemical analysis of water, urine and blood/plasma, as well as results of the genotyping analysis are included in dbGaP. Data generated by metabolomics and epigenetic analyses in small subsets of the Chihuahua cohort are not included, but are available in published articles.

  Study phs002139

• Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C)

  Reprinted from http://www.haltctrial.org/ Purpose The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial is a randomized controlled trial designed to evaluate the safety and efficacy of long-term use of pegylated interferon for the treatment of chronic hepatitis C in patients who failed to respond to previous interferon therapy. The HALT-C Trial was developed to determine whether prolonged interferon therapy altered histological and clinical outcomes in a group of patients who had failed to eradicate hepatitis C virus with previous interferon treatment. Study Hypotheses In patients with chronic hepatitis C and bridging fibrosis who failed to eradicate the virus with previous interferon therapy, long-term treatment with interferon is safe and can prevent progression to cirrhosis. In patients with cirrhosis secondary to chronic hepatitis C who failed to eradicate the virus with previous interferon therapy, long-term treatment with interferon is safe and can reduce the risks of hepatic decompensation or of hepatocellular carcinoma. Study Design 1145 patients with chronic HCV and advanced hepatic fibrosis (Ishak stage 3-6) who failed to respond to previous treatment with interferon were enrolled at 10 clinical centers and entered into a Lead-in phase. They were treated with a combination of pegylated interferon (Pegasys&#174;, Hoffmann-La Roche) 180 &#181;g/week and ribavirin (1000-1200 mg/day) for 24 weeks. Patients who had no detectable HCV-RNA at week 20 continued on combination therapy until week 48. 662 patients who did not clear virus were randomly assigned at week 24 to either continue treatment with pegylated interferon alone (90 &#181;g/week) for an additional 42 months, or to have treatment discontinued. All patients were followed at 3-month intervals following randomization. Liver biopsy was performed at baseline and after 1.5 and 3.5 years of treatment. Because of slower than expected enrollment and the approval by the FDA of peginterferon alfa-2b after the start of the trial, we modified the study protocol in three ways. First, criteria for admission to the trial were liberalized to allow patients to enter the trial with lower platelet and white blood cell counts than had been initially considered safe or tolerable. Second, 151 Lead-in patients and those continuing on therapy after 24 weeks who demonstrated return of viremia during or after their 48-week treatment period (called "Breakthrough" or "Relapse" patients, respectively) were allowed to return to enter the randomized trial. Third, 237 patients treated with peginterferon alfa-2b (or with peginterferon alfa-2a in licensing trials) outside the HALT-C Trial who in other respects met all study criteria, having received the equivalent of Trial Lead-in period therapy, were allowed to enter the long-term trial as "Express" patients. A total 1050 patients were randomized. Those patients who completed Month 48 were offered an "extended follow-up (observation only)" until October 2009. These visits will primarily be to identify outcome events, and to provide information to patients concerning the current status of the trial. Some questionnaires, blood tests, and an ultrasonogram will be performed. Quarterly (every 3 months) Interval history of complications, adverse events Current medications Brief physical examination Laboratory tests: liver panel, CBC, INR, AFP Child-Pugh Score Stored serum Annual Complete physical examination Ultrasound of liver 1.5 years (M24 visit, middle of study) Liver biopsy: formalin fixed histology, frozen liver tissue (subset of patients) 3.5 years (M48, end of study) Liver biopsy: formalin fixed histology, frozen liver tissue (subset of patients) Endoscopy: evaluate esophageal varices and portal hypertension After Month 48 Observation only (no treatment) to determine clinical outcomes Clinic visit every 6 months with current medications, brief PE, liver panel, CBC, AFP, stored Serum Ultrasound of liver every 6 months Outcome Variables Primary outcome variables to be assessed in the two groups of patients include: Development of cirrhosis on liver biopsy (progression of Ishak fibrosis score by 2 points or more) Development of hepatic decompensation, as shown by: Sustained increase in the Child-Turcotte-Pugh score to 7 points or higher Variceal hemorrhage Ascites Spontaneous bacterial peritonitis Hepatic encephalopathy Development of hepatocellular carcinoma Death Secondary outcomes include quality of life, serious adverse events, events requiring dose reductions, and development of presumed hepatocellular carcinoma.

  Study phs000430

• Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) - Genome-Wide Association Study Meta-Analysis

  Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) was one of five projects funded in 2010 as part of the NCI&#39;s Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative (http://epi.grants.cancer.gov/gameon/). GAME-ON&#39;s overall goal was to foster an intra-disciplinary and collaborative approach to the translation of promising research leads deriving from the initial wave of cancer GWAS. Specific goals included replication of previous GWAS findings and identification of new susceptibility loci through meta analyses of existing GWAS data and fine mapping of identified loci to better pinpoint causal variants; and identify germline variants that are associated with risk of multiple cancers. The other four funded GAME-ON projects were: the ColoRectal TransdisciplinaryStudy (CORECT), Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE), Follow-up of Ovarian Cancer Genetic Association and Interaction Study (FOCI), and Transdisciplinary Research in Cancer of the Lung (TRICL). To identify additional cancer risk loci, improve the precision of fine-mapping, and facilitate cross-cancer analyses, DRIVE investigators performed a meta-analysis of eleven genome-wide association studies of breast cancer: The Australian Breast Cancer Family Study (ABCFS), the British Breast Cancer Study (BBCS), the Breast and Prostate Cancer Cohort Consortium (BPC3), the Breast Cancer Family Registries (BCFR), the Dutch Familial Bilateral Breast Cancer Study (DFBBCS), German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), the Helsinki breast cancer family Study (HEBCS), the Mammary Carcinoma Risk factor Investigation (MARIE), the Singapore and Sweden Breast Cancer Study (SASBAC), the Triple Negative Breast Cancer Study (TNBC), and the UK2 GWAS. These studies comprised a total of 16,062 cases and 46,157 controls. Imputation to the 1,000 Genomes Project Phase 1 v3 ALL reference panel was performed by study, and summary statistics from each study were combined using fixed-effect meta analysis.

  Study phs001263

• Somatic Mutations and Their Etiological Determinants for Breast Cancer in African American Women (B-CAUSE Study)

  The breast cancer health disparity between women of African ancestry (AA) and European ancestry (EA) remains a major public health challenge in the United States. AA women are afflicted by higher rate of triple-negative breast cancer (TNBC) and bear the highest mortality rate of all populations from the disease. Even within TNBC, some data suggest that AA women have poorer outcomes than EA women. Mounting evidence points to population differences in cancer biology, a fundamental question that remains unsettled. The disparity also manifests in representativeness in tumor sequencing projects, due to the low inclusion of AAs in genomic studies. A recent analysis of The Cancer Genome Atlas (TCGA) data revealed that the number of AA cases sequenced was sufficient only for studying frequently mutated genes (&#8805;10%), and the power was worse for TNBC as a separate disease entity. As a result, the breast tumor mutational landscape elucidated to date is derived mostly from EA cases, and may not necessarily represent AA cancer genomes. Moreover, as discovery potential for new driver genes has come close to a plateau, cancer in AAs derived from distinct genetic and environmental contexts may provide a powerful venue for discovering mutations that are rare in EA cases. This is showcased in recent studies in colon and prostate cancer. Thus, we carried out a collaborative project, B-CAUSE, to characterize the mutational landscape of AA breast cancer genomes by pooling resources from five established studies, including the Women's Circle of Health Study (WCHS), the Black Women's Health Study (BWHS), the Southern Community Cohort Study (SCCS), the Nashville Breast Health Study (NBHS), and the Southern Tri-State Breast Health Study (STSBHS). This effort has created the largest AA-specific breast tumor mutation dataset to date in an efficient manner. The data deposited here are from the whole-exome sequencing (WES) of matched tumor-normal pairs of 462 TNBC in AA women from the B-CAUSE Study.

  Study phs003962

• Reduced Representation Bisulfite Sequencing (RRBS) in various tissues to discover DNA methylation markers for the diagnosis of breast and ovarian cancer.

  Despite a myriad of attempts in the last three decades to diagnose ovarian cancer (OC) earlier, this clinical aim still remains a significant challenge. In addition, monitoring treatment and early detection of fatal breast cancer (BC) remains a major unmet need. Aberrant methylation patterns of linked CpGs analyzed in DNA fragments shed by cancers into the bloodstream (i.e. cell-free DNA) can provide highly specific signals indicating cancer presence.In order to discover the most relevant CpG regions, we used RRBS and analysed several tissue samples: 11 prospectively collected invasive epithelial ovarian cancer samples (high grade serous n=8, low grade serous n=1, endometrioid n=1, mucinous n=1, mean age = 54.7 years), 8 prospectively collected invasive ductal breast cancer samples (2/8 triple negative; mean age = 56.6 years), one benign tumor (papillary serous cystadenoma, age = 86 years), 18 non-neoplastic tissue samples (breast n=7 and adnexal n=11, mean age = 60.2 years), two non-neoplastic endometrial tissues (mean age = 68 years) and twenty three white blood cell samples (mean age = 57.8 years) were assessed by RRBS. Genome wide methylation analysis was performed by Reduced Representation Bisulfite Sequencing (RRBS) at GATC Biotech. DNA was digested with MspI followed by size selection of the library, providing enhanced coverage for the CpG-rich regions. The digested DNA was adapter ligated, bisulfite modified and PCR amplified. The libraries were sequenced on Illumina’s HiSeq 2500. Analysis of the first samples sequenced with 100bp paired-end mode showed that the library insert size was small. Therefore, the remaining samples were sequenced with 50 bp paired-end mode. Using Genedata Expressionist® for Genomic Profiling v9.1, we established a bioinformatics pipeline for the detection of cancer specific differentially methylated regions (DMRs). The most promising DMRs were taken forward for the development and validation of serum based clinical assays.

  Study EGAS00001002609

• OncoArray: Prostate Cancer

  Original description of the study: From ELLIPSE (linked to the PRACTICAL consortium), we contributed ~78,000 SNPs to the OncoArray. A large fraction of the content was derived from the GWAS meta-analyses in European ancestry populations (overall and aggressive disease; ~27K SNPs). We also selected just over 10,000 SNPs from the meta-analyses in the non-European populations, with a majority of these SNPs coming from the analysis of overall prostate cancer in African ancestry populations as well as from the multiethnic meta-analysis. A substantial fraction of SNPs (~28,000) were also selected for fine-mapping of 53 loci not included in the common fine-mapping regions (tagging at r2&#62;0.9 across &#177;500kb regions). We also selected a few thousand SNPs related with PSA levels and/or disease survival as well as SNPs from candidate lists provided by study collaborators, as well as from meta-analyses of exome SNP chip data from the Multiethnic Cohort and UK studies. The Contributing Studies: Aarhus: Hospital-based, Retrospective, Observational. Source of cases: Patients treated for prostate adenocarcinoma at Department of Urology, Aarhus University Hospital, Skejby (Aarhus, Denmark). Source of controls: Age-matched males treated for myocardial infarction or undergoing coronary angioplasty, but with no prostate cancer diagnosis based on information retrieved from the Danish Cancer Register and the Danish Cause of Death Register. AHS: Nested case-control study within prospective cohort. Source of cases: linkage to cancer registries in study states. Source of controls: matched controls from cohort ATBC: Prospective, nested case-control. Source of cases: Finnish male smokers aged 50-69 years at baseline. Source of controls: Finnish male smokers aged 50-69 years at baseline BioVu: Cases identified in a biobank linked to electronic health records. Source of cases: A total of 214 cases were identified in the VUMC de-identified electronic health records database (the Synthetic Derivative) and shipped to USC for genotyping in April 2014. The following criteria were used to identify cases: Age 18 or greater; male; African Americans (Black) only. Note that African ancestry is not self-identified, it is administratively or third-party assigned (which has been shown to be highly correlated with genetic ancestry for African Americans in BioVU; see references). Source of controls: Controls were identified in the de-identified electronic health record. Unfortunately, they were not age matched to the cases, and therefore cannot be used for this study. Canary PASS: Prospective, Multi-site, Observational Active Surveillance Study. Source of cases: clinic based from Beth Israel Deaconness Medical Center, Eastern Virginia Medical School, University of California at San Francisco, University of Texas Health Sciences Center San Antonio, University of Washington, VA Puget Sound. Source of controls: N/A CCI: Case series, Hospital-based. Source of cases: Cases identified through clinics at the Cross Cancer Institute. Source of controls: N/A CerePP French Prostate Cancer Case-Control Study (ProGene): Case-Control, Prospective, Observational, Hospital-based. Source of cases: Patients, treated in French departments of Urology, who had histologically confirmed prostate cancer. Source of controls: Controls were recruited as participating in a systematic health screening program and found unaffected (normal digital rectal examination and total PSA &#60; 4 ng/ml, or negative biopsy if PSA &#62; 4 ng/ml). COH: hospital-based cases and controls from outside. Source of cases: Consented prostate cancer cases at City of Hope. Source of controls: Consented unaffected males that were part of other studies where they consented to have their DNA used for other research studies. COSM: Population-based cohort. Source of cases: General population. Source of controls: General population CPCS1: Case-control - Denmark. Source of cases: Hospital referrals. Source of controls: Copenhagen General Population Study CPCS2: Source of cases: Hospital referrals. Source of controls: Copenhagen General Population Study CPDR: Retrospective cohort. Source of cases: Walter Reed National Military Medical Center. Source of controls: Walter Reed National Military Medical Center ACS_CPS-II: Nested case-control derived from a prospective cohort study. Source of cases: Identified through self-report on follow-up questionnaires and verified through medical records or cancer registries, identified through cancer registries or the National Death Index (with prostate cancer as the primary cause of death). Source of controls: Cohort participants who were cancer-free at the time of diagnosis of the matched case, also matched on age (&#177;6 mo) and date of biospecimen donation (&#177;6 mo). EPIC: Case-control - Germany, Greece, Italy, Netherlands, Spain, Sweden, UK. Source of cases: Identified through record linkage with population-based cancer registries in Italy, the Netherlands, Spain, Sweden and UK. In Germany and Greece, follow-up is active and achieved through checks of insurance records and cancer and pathology registries as well as via self-reported questionnaires; self-reported incident cancers are verified through medical records. Source of controls: Cohort participants without a diagnosis of cancer EPICAP: Case-control, Population-based, ages less than 75 years at diagnosis, H&#233;rault, France. Source of cases: Prostate cancer cases in all public hospitals and private urology clinics of d&#233;partement of H&#233;rault in France. Cases validation by the H&#233;rault Cancer Registry. Source of controls: Population-based controls, frequency age matched (5-year groups). Quotas by socio-economic status (SES) in order to obtain a distribution by SES among controls identical to the SES distribution among general population men, conditionally to age. ERSPC: Population-based randomized trial. Source of cases: Men with PrCa from screening arm ERSPC Rotterdam. Source of controls: Men without PrCa from screening arm ERSPC Rotterdam ESTHER: Case-control, Prospective, Observational, Population-based. Source of cases: Prostate cancer cases in all hospitals in the state of Saarland, from 2001-2003. Source of controls: Random sample of participants from routine health check-up in Saarland, in 2000-2002 FHCRC: Population-based, case-control, ages 35-74 years at diagnosis, King County, WA, USA. Source of cases: Identified through the Seattle-Puget Sound SEER cancer registry. Source of controls: Randomly selected, age-frequency matched residents from the same county as cases Gene-PARE: Hospital-based. Source of cases: Patients that received radiotherapy for treatment of prostate cancer. Source of controls: n/a Hamburg-Zagreb: Hospital-based, Prospective. Source of cases: Prostate cancer cases seen at the Department of Oncology, University Hospital Center Zagreb, Croatia. Source of controls: Population-based (Croatia), healthy men, older than 50, with no medical record of cancer, and no family history of cancer (1st &#38; 2nd degree relatives) HPFS: Nested case-control. Source of cases: Participants of the HPFS cohort. Source of controls: Participants of the HPFS cohort IMPACT: Observational. Source of cases: Carriers and non-carriers (with a known mutation in the family) of the BRCA1 and BRCA2 genes, aged between 40 and 69, who are undergoing prostate screening with annual PSA testing. This cohort has been diagnosed with prostate cancer during the study. Source of controls: Carriers and non-carriers (with a known mutation in the family) of the BRCA1 and BRCA2 genes, aged between 40 and 69, who are undergoing prostate screening with annual PSA testing. This cohort has not been diagnosed with prostate cancer during the study. IPO-Porto: Hospital-based. Source of cases: Early onset and/or familial prostate cancer. Source of controls: Blood donors Karuprostate: Case-control, Retrospective, Population-based. Source of cases: From FWI (Guadeloupe): 237 consecutive incident patients with histologically confirmed prostate cancer attending public and private urology clinics; From Democratic Republic of Congo: 148 consecutive incident patients with histologically confirmed prostate cancer attending the University Clinic of Kinshasa. Source of controls: From FWI (Guadeloupe): 277 controls recruited from men participating in a free systematic health screening program open to the general population; From Democratic Republic of Congo: 134 controls recruited from subjects attending the University Clinic of Kinshasa KULEUVEN: Hospital-based, Prospective, Observational. Source of cases: Prostate cancer cases recruited at the University Hospital Leuven. Source of controls: Healthy males with no history of prostate cancer recruited at the University Hospitals, Leuven. LAAPC: Subjects were participants in a population-based case-control study of aggressive prostate cancer conducted in Los Angeles County. Cases were identified through the Los Angeles County Cancer Surveillance Program rapid case ascertainment system. Eligible cases included African American, Hispanic, and non-Hispanic White men diagnosed with a first primary prostate cancer between January 1, 1999 and December 31, 2003. Eligible cases also had (a) prostatectomy with documented tumor extension outside the prostate, (b) metastatic prostate cancer in sites other than prostate, (c) needle biopsy of the prostate with Gleason grade &#8805;8, or (d) needle biopsy with Gleason grade 7 and tumor in more than two thirds of the biopsy cores. Eligible controls were men never diagnosed with prostate cancer, living in the same neighborhood as a case, and were frequency matched to cases on age (&#177; 5 y) and race/ethnicity. Controls were identified by a neighborhood walk algorithm, which proceeds through an obligatory sequence of adjacent houses or residential units beginning at a specific residence that has a specific geographic relationship to the residence where the case lived at diagnosis. Malaysia: Case-control. Source of cases: Patients attended the outpatient urology or uro-onco clinic at University Malaya Medical Center. Source of controls: Population-based, age matched (5-year groups), ascertained through electoral register, Subang Jaya, Selangor, Malaysia MCC-Spain: Case-control. Source of cases: Identified through the urology departments of the participating hospitals. Source of controls: Population-based, frequency age and region matched, ascertained through the rosters of the primary health care centers MCCS: Nested case-control, Melbourne, Victoria. Source of cases: Identified by linkage to the Victorian Cancer Registry. Source of controls: Cohort participants without a diagnosis of cancer MD Anderson: Participants in this study were identified from epidemiological prostate cancer studies conducted at the University of Texas MD Anderson Cancer Center in the Houston Metropolitan area. Cases were accrued in the Houston Medical Center and were not restricted with respect to Gleason score, stage or PSA. Controls were identified via random-digit-dialing or among hospital visitors and they were frequency matched to cases on age and race. Lifestyle, demographic, and family history data were collected using a standardized questionnaire. MDACC_AS: A prospective cohort study. Source of cases: Men with clinically organ-confined prostate cancer meeting eligibility criteria for a prospective cohort study of active surveillance at MD Anderson Cancer Center. Source of controls: N/A MEC: The Multiethnic Cohort (MEC) is comprised of over 215,000 men and women recruited from Hawaii and the Los Angeles area between 1993 and 1996. Between 1995 and 2006, over 65,000 blood samples were collected from participants for genetic analyses. To identify incident cancer cases, the MEC was cross-linked with the population-based Surveillance, Epidemiology and End Results (SEER) registries in California and Hawaii, and unaffected cohort participants with blood samples were selected as controls MIAMI (WFPCS): Prostate cancer cases and controls were recruited from the Departments of Urology and Internal Medicine of the Wake Forest University School of Medicine using sequential patient populations as described previously (PMID:15342424). All study subjects received a detailed description of the study protocol and signed their informed consent, as approved by the medical center&#39;s Institutional Review Board. The general eligibility criteria were (i) able to comprehend informed consent and (ii) without previously diagnosed cancer. The exclusion criteria were (i) clinical diagnosis of autoimmune diseases; (ii) chronic inflammatory conditions; and (iii) infections within the past 6 weeks. Blood samples were collected from all subjects. MOFFITT: Hospital-based. Source of cases: clinic based from Moffitt Cancer Center. Source of controls: Moffitt Cancer Center affiliated Lifetime cancer screening center NMHS: Case-control, clinic based, Nashville TN. Source of cases: All urology clinics in Nashville, TN. Source of controls: Men without prostate cancer at prostate biopsy. PCaP: The North Carolina-Louisiana Prostate Cancer Project (PCaP) is a multidisciplinary population-based case-only study designed to address racial differences in prostate cancer through a comprehensive evaluation of social, individual and tumor level influences on prostate cancer aggressiveness. PCaP enrolled approximately equal numbers of African Americans and Caucasian Americans with newly-diagnosed prostate cancer from North Carolina (42 counties) and Louisiana (30 parishes) identified through state tumor registries. African American PCaP subjects with DNA, who agreed to future use of specimens for research, participated in OncoArray analysis. PCMUS: Case-control - Sofia, Bulgaria. Source of cases: Patients of Clinic of Urology, Alexandrovska University Hospital, Sofia, Bulgaria, PrCa histopathologically confirmed. Source of controls: 72 patients with verified BPH and PSA&#60;3,5; 78 healthy controls from the MMC Biobank, no history of PrCa PHS: Nested case-control. Source of cases: Participants of the PHS1 trial/cohort. Source of controls: Participants of the PHS1 trial/cohort PLCO: Nested case-control. Source of cases: Men with a confirmed diagnosis of prostate cancer from the PLCO Cancer Screening Trial. Source of controls: Controls were men enrolled in the PLCO Cancer Screening Trial without a diagnosis of cancer at the time of case ascertainment. Poland: Case-control. Source of cases: men with unselected prostate cancer, diagnosed in north-western Poland at the University Hospital in Szczecin. Source of controls: cancer-free men from the same population, taken from the healthy adult patients of family doctors in the Szczecin region PROCAP: Population-based, Retrospective, Observational. Source of cases: Cases were ascertained from the National Prostate Cancer Register of Sweden Follow-Up Study, a retrospective nationwide cohort study of patients with localized prostate cancer. Source of controls: Controls were selected among men referred for PSA testing in laboratories in Stockholm County, Sweden, between 2010 and 2012. PROGReSS: Hospital-based, Prospective, Observational. Source of cases: Prostate cancer cases from the Hospital Cl&#237;nico Universitario de Santiago de Compostela, Galicia, Spain. Source of controls: Cancer-free men from the same population ProMPT: A study to collect samples and data from subjects with and without prostate cancer. Retrospective, Experimental. Source of cases: Subjects attending outpatient clinics in hospitals. Source of controls: Subjects attending outpatient clinics in hospitals ProtecT: Trial of treatment. Samples taken from subjects invited for PSA testing from the community at nine centers across United Kingdom. Source of cases: Subjects who have a proven diagnosis of prostate cancer following testing. Source of controls: Identified through invitation of subjects in the community. PROtEuS: Case-control, population-based. Source of cases: All new histologically-confirmed cases, aged less or equal to 75 years, diagnosed between 2005 and 2009, actively ascertained across Montreal French hospitals. Source of controls: Randomly selected from the Provincial electoral list of French-speaking men between 2005 and 2009, from the same area of residence as cases and frequency-matched on age. QLD: Case-control. Source of cases: A longitudinal cohort study (Prostate Cancer Supportive Care and Patient Outcomes Project: ProsCan) conducted in Queensland, through which men newly diagnosed with prostate cancer from 26 private practices and 10 public hospitals were directly referred to ProsCan at the time of diagnosis by their treating clinician (age range 43-88 years). All cases had histopathologically confirmed prostate cancer, following presentation with an abnormal serum PSA and/or lower urinary tract symptoms. Source of controls: Controls comprised healthy male blood donors with no personal history of prostate cancer, recruited through (i) the Australian Red Cross Blood Services in Brisbane (age range 19-76 years) and (ii) the Australian Electoral Commission (AEC) (age and post-code/ area matched to ProsCan, age range 54-90 years). RAPPER: Multi-centre, hospital based blood sample collection study in patients enrolled in clinical trials with prospective collection of radiotherapy toxicity data. Source of cases: Prostate cancer patients enrolled in radiotherapy trials: CHHiP, RT01, Dose Escalation, RADICALS, Pelvic IMRT, PIVOTAL. Source of controls: N/A SABOR: Prostate Cancer Screening Cohort. Source of cases: Men &#62;45 yrs of age participating in annual PSA screening. Source of controls: Males participating in annual PSA prostate cancer risk evaluations (funded by NCI biomarkers discovery and validation grant), recruited through University of Texas Health Science Center at San Antonio and affiliated sites or through study advertisements, enrolment open to the community SCCS: Case-control in cohort, Southeastern USA. Prospective, Observational, Population-based. Source of cases: SCCS entry population. Source of controls: SCCS entry population SCPCS: Population-based, Retrospective, Observational. Source of cases: South Carolina Central Cancer Registry. Source of controls: Health Care Financing Administration beneficiary file SEARCH: Case-control - East Anglia, UK. Source of cases: Men &#60; 70 years of age registered with prostate cancer at the population-based cancer registry, Eastern Cancer Registration and Information Centre, East Anglia, UK. Source of controls: Men attending general practice in East Anglia with no known prostate cancer diagnosis, frequency matched to cases by age and geographic region SNP_Prostate_Ghent: Hospital-based, Retrospective, Observational. Source of cases: Men treated with IMRT as primary or postoperative treatment for prostate cancer at the Ghent University Hospital between 2000 and 2010. Source of controls: Employees of the University hospital and members of social activity clubs, without a history of any cancer. SPAG: Hospital-based, Retrospective, Observational. Source of cases: Guernsey. Source of controls: Guernsey STHM2: Population-based, Retrospective, Observational. Source of cases: Cases were selected among men referred for PSA testing in laboratories in Stockholm County, Sweden, between 2010 and 2012. Source of controls: Controls were selected among men referred for PSA testing in laboratories in Stockholm County, Sweden, between 2010 and 2012. PCPT: Case-control from a randomized clinical trial. Source of cases: Randomized clinical trial. Source of controls: Randomized clinical trial SELECT: Case-cohort from a randomized clinical trial. Source of cases: Randomized clinical trial. Source of controls: Randomized clinical trial TAMPERE: Case-control - Finland, Retrospective, Observational, Population-based. Source of cases: Identified through linkage to the Finnish Cancer Registry and patient records; and the Finnish arm of the ERSPC study. Source of controls: Cohort participants without a diagnosis of cancer UGANDA: Uganda Prostate Cancer Study: Uganda is a case-control study of prostate cancer in Kampala Uganda that was initiated in 2011. Men with prostate cancer were enrolled from the Urology unit at Mulago Hospital and men without prostate cancer (i.e. controls) were enrolled from other clinics (i.e. surgery) at the hospital. UKGPCS: ICR, UK. Source of cases: Cases identified through clinics at the Royal Marsden hospital and nationwide NCRN hospitals. Source of controls: Ken Muir&#39;s control- 2000 ULM: Case-control - Germany. Source of cases: familial cases (n=162): identified through questionnaires for family history by collaborating urologists all over Germany; sporadic cases (n=308): prostatectomy series performed in the Clinic of Urology Ulm between 2012 and 2014. Source of controls: age-matched controls (n=188): age-matched men without prostate cancer and negative family history collected in hospitals of Ulm WUGS/WUPCS: Cases Series, USA. Source of cases: Identified through clinics at Washington University in St. Louis. Source of controls: Men diagnosed and managed with prostate cancer in University based clinic. Acknowledgement Statements: Aarhus: This study was supported by the Danish Strategic Research Council (now Innovation Fund Denmark) and the Danish Cancer Society. The Danish Cancer Biobank (DCB) is acknowledged for biological material. AHS: This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics (Z01CP010119). ATBC: This research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. Additionally, this research was supported by U.S. Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C, and HHSN261201500005C from the National Cancer Institute, Department of Health and Human Services. BioVu: The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center&#39;s BioVU which is supported by institutional funding and by the National Center for Research Resources, Grant UL1 RR024975-01 (which is now at the National Center for Advancing Translational Sciences, Grant 2 UL1 TR000445-06). Canary PASS: PASS was supported by Canary Foundation and the National Cancer Institute&#39;s Early Detection Research Network (U01 CA086402) CCI: This work was awarded by Prostate Cancer Canada and is proudly funded by the Movember Foundation - Grant # D2013-36.The CCI group would like to thank David Murray, Razmik Mirzayans, and April Scott for their contribution to this work. CerePP French Prostate Cancer Case-Control Study (ProGene): None reported COH: SLN is partially supported by the Morris and Horowitz Families Endowed Professorship COSM: The Swedish Research Council, the Swedish Cancer Foundation CPCS1 &#38; CPCS2: Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, DenmarkCPCS1 would like to thank the participants and staff of the Copenhagen General Population Study for their important contributions. CPDR: Uniformed Services University for the Health Sciences HU0001-10-2-0002 (PI: David G. McLeod, MD) CPS-II: The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study II cohort. CPS-II thanks the participants and Study Management Group for their invaluable contributions to this research. We would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. EPIC: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by the Danish Cancer Society (Denmark); the Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation, Greek Ministry of Health; Greek Ministry of Education (Greece); the Italian Association for Research on Cancer (AIRC) and National Research Council (Italy); the Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF); the Statistics Netherlands (The Netherlands); the Health Research Fund (FIS), Regional Governments of Andaluc&#237;a, Asturias, Basque Country, Murcia and Navarra, Spanish Ministry of Health ISCIII RETIC (RD06/0020), Red de Centros RCESP, C03/09 (Spain); the Swedish Cancer Society, Swedish Scientific Council and Regional Government of Sk&#229;ne and V&#228;sterbotten, Fundacion Federico SA (Sweden); the Cancer Research UK, Medical Research Council (United Kingdom). EPICAP: The EPICAP study was supported by grants from Ligue Nationale Contre le Cancer, Ligue d&#233;partementale du Val de Marne; Fondation de France; Agence Nationale de s&#233;curit&#233; sanitaire de l&#39;alimentation, de l&#39;environnement et du travail (ANSES). The EPICAP study group would like to thank all urologists, Antoinette Anger and Hasina Randrianasolo (study monitors), Anne-Laure Astolfi, Coline Bernard, Oriane Noyer, Marie-H&#233;l&#232;ne De Campo, Sandrine Margaroline, Louise N&#39;Diaye, and Sabine Perrier-Bonnet (Clinical Research nurses). ERSPC: This study was supported by the DutchCancerSociety (KWF94-869,98-1657,2002-277,2006-3518, 2010-4800), The Netherlands Organisation for Health Research and Development (ZonMW-002822820, 22000106, 50-50110-98-311, 62300035), The Dutch Cancer Research Foundation (SWOP), and an unconditional grant from Beckman-Coulter-HybritechInc. ESTHER: The ESTHER study was supported by a grant from the Baden W&#252;rttemberg Ministry of Science, Research and Arts. The ESTHER group would like to thank Hartwig Ziegler, Sonja Wolf, Volker Hermann, Heiko M&#252;ller, Karina Dieffenbach, Katja Butterbach for valuable contributions to the study. FHCRC: The FHCRC studies were supported by grants R01-CA056678, R01-CA082664, and R01-CA092579 from the US National Cancer Institute, National Institutes of Health, with additional support from the Fred Hutchinson Cancer Research Center. FHCRC would like to thank all the men who participated in these studies. Gene-PARE: The Gene-PARE study was supported by grants 1R01CA134444 from the U.S. National Institutes of Health, PC074201 and W81XWH-15-1-0680 from the Prostate Cancer Research Program of the Department of Defense and RSGT-05-200-01-CCE from the American Cancer Society. Hamburg-Zagreb: None reported HPFS: The Health Professionals Follow-up Study was supported by grants UM1CA167552, CA133891, CA141298, and P01CA055075. HPFS are grateful to the participants and staff of the Physicians&#39; Health Study and Health Professionals Follow-Up Study for their valuable contributions, as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. IMPACT: The IMPACT study was funded by The Ronald and Rita McAulay Foundation, CR-UK Project grant (C5047/A1232), Cancer Australia, AICR Netherlands A10-0227, Cancer Australia and Cancer Council Tasmania, NIHR, EU Framework 6, Cancer Councils of Victoria and South Australia, and Philanthropic donation to Northshore University Health System. We acknowledge support from the National Institute for Health Research (NIHR) to the Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden Foundation NHS Trust. IMPACT acknowledges the IMPACT study steering committee, collaborating centres, and participants. IPO-Porto: The IPO-Porto study was funded by Funda&#231;&#228;o para a Ci&#234;ncia e a Tecnologia (FCT; UID/DTP/00776/2013 and PTDC/DTP-PIC/1308/2014) and by IPO-Porto Research Center (CI-IPOP-16-2012 and CI-IPOP-24-2015). MC and MPS are research fellows from Liga Portuguesa Contra o Cancro, N&#250;cleo Regional do Norte. SM is a research fellow from FCT (SFRH/BD/71397/2010). IPO-Porto would like to express our gratitude to all patients and families who have participated in this study. Karuprostate: The Karuprostate study was supported by the the Frech National Health Directorate and by the Association pour la Recherche sur les Tumeurs de la ProstateKarusprostate thanks S&#233;verine Ferdinand. KULEUVEN: F.C. and S.J. are holders of grants from FWO Vlaanderen (G.0684.12N and G.0830.13N), the Belgian federal government (National Cancer Plan KPC_29_023), and a Concerted Research Action of the KU Leuven (GOA/15/017). TVDB is holder of a doctoral fellowship of the FWO. LAAPC: This study was funded by grant R01CA84979 (to S.A. Ingles) from the National Cancer Institute, National Institutes of Health. Malaysia: The study was funded by the University Malaya High Impact Research Grant (HIR/MOHE/MED/35). Malaysia thanks all associates in the Urology Unit, University of Malaya, Cancer Research Initiatives Foundation (CARIF) and the Malaysian Men&#39;s Health Initiative (MMHI). MCCS: MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553, and 504711, and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. MCC-Spain: The study was partially funded by the Accion Transversal del Cancer, approved on the Spanish Ministry Council on the 11th October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI09/00773-Cantabria, PI11/01889-FEDER, PI12/00265, PI12/01270, and PI12/00715), by the Fundaci&#243;n Marqu&#233;s de Valdecilla (API 10/09), by the Spanish Association Against Cancer (AECC) Scientific Foundation and by the Catalan Government DURSI grant 2009SGR1489. Samples: Biological samples were stored at the Parc de Salut MAR Biobank (MARBiobanc; Barcelona) which is supported by Instituto de Salud Carlos III FEDER (RD09/0076/00036). Also sample collection was supported by the Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d&#39;Oncologia de Catalunya (XBTC). MCC-Spain acknowledges the contribution from Esther Gracia-Lavedan in preparing the data. We thank all the subjects who participated in the study and all MCC-Spain collaborators. MD Anderson: Prostate Cancer Case-Control Studies at MD Anderson (MDA) supported by grants CA68578, ES007784, DAMD W81XWH-07-1-0645, and CA140388. MDACC_AS: None reported MEC: Funding provided by NIH grant U19CA148537 and grant U01CA164973. MIAMI (WFPCS): ACS MOFFITT: The Moffitt group was supported by the US National Cancer Institute (R01CA128813, PI: J.Y. Park). NMHS: Funding for the Nashville Men&#39;s Health Study (NMHS) was provided by the National Institutes of Health Grant numbers: RO1CA121060. PCaP only data: The North Carolina - Louisiana Prostate Cancer Project (PCaP) is carried out as a collaborative study supported by the Department of Defense contract DAMD 17-03-2-0052. For HCaP-NC follow-up data: The Health Care Access and Prostate Cancer Treatment in North Carolina (HCaP-NC) study is carried out as a collaborative study supported by the American Cancer Society award RSGT-08-008-01-CPHPS. For studies using both PCaP and HCaP-NC follow-up data please use: The North Carolina - Louisiana Prostate Cancer Project (PCaP) and the Health Care Access and Prostate Cancer Treatment in North Carolina (HCaP-NC) study are carried out as collaborative studies supported by the Department of Defense contract DAMD 17-03-2-0052 and the American Cancer Society award RSGT-08-008-01-CPHPS, respectively. For any PCaP data, please include: The authors thank the staff, advisory committees and research subjects participating in the PCaP study for their important contributions. For studies using PCaP DNA/genotyping data, please include: We would like to acknowledge the UNC BioSpecimen Facility and LSUHSC Pathology Lab for our DNA extractions, blood processing, storage and sample disbursement (https://genome.unc.edu/bsp). For studies using PCaP tissue, please include: We would like to acknowledge the RPCI Department of Urology Tissue Microarray and Immunoanalysis Core for our tissue processing, storage and sample disbursement. For studies using HCaP-NC follow-up data, please use: The Health Care Access and Prostate Cancer Treatment in North Carolina (HCaP-NC) study is carried out as a collaborative study supported by the American Cancer Society award RSGT-08-008-01-CPHPS. The authors thank the staff, advisory committees and research subjects participating in the HCaP-NC study for their important contributions. For studies that use both PCaP and HCaP-NC, please use: The authors thank the staff, advisory committees and research subjects participating in the PCaP and HCaP-NC studies for their important contributions. PCMUS: The PCMUS study was supported by the Bulgarian National Science Fund, Ministry of Education and Science (contract DOO-119/2009; DUNK01/2-2009; DFNI-B01/28/2012) with additional support from the Science Fund of Medical University - Sofia (contract 51/2009; 8I/2009; 28/2010). PHS: The Physicians&#39; Health Study was supported by grants CA34944, CA40360, CA097193, HL26490, and HL34595. PHS members are grateful to the participants and staff of the Physicians&#39; Health Study and Health Professionals Follow-Up Study for their valuable contributions, as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. PLCO: This PLCO study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIHPLCO thanks Drs. Christine Berg and Philip Prorok, Division of Cancer Prevention at the National Cancer Institute, the screening center investigators and staff of the PLCO Cancer Screening Trial for their contributions to the PLCO Cancer Screening Trial. We thank Mr. Thomas Riley, Mr. Craig Williams, Mr. Matthew Moore, and Ms. Shannon Merkle at Information Management Services, Inc., for their management of the data and Ms. Barbara O&#39;Brien and staff at Westat, Inc. for their contributions to the PLCO Cancer Screening Trial. We also thank the PLCO study participants for their contributions to making this study possible. Poland: None reported PROCAP: PROCAP was supported by the Swedish Cancer Foundation (08-708, 09-0677). PROCAP thanks and acknowledges all of the participants in the PROCAP study. We thank Carin Cavalli-Bj&#246;rkman and Ami R&#246;nnberg Karlsson for their dedicated work in the collection of data. Michael Broms is acknowledged for his skilful work with the databases. KI Biobank is acknowledged for handling the samples and for DNA extraction. We acknowledge The NPCR steering group: P&#228;r Stattin (chair), Anders Widmark, Stefan Karlsson, Magnus T&#246;rnblom, Jan Adolfsson, Anna Bill-Axelson, Ove Andr&#233;n, David Robinson, Bill Pettersson, Jonas Hugosson, Jan-Erik Damber, Ola Bratt, G&#246;ran Ahlgren, Lars Egevad, and Roy Ehrnstr&#246;m. PROGReSS: The PROGReSS study is founded by grants from the Spanish Ministry of Health (INT15/00070; INT16/00154; FIS PI10/00164, FIS PI13/02030; FIS PI16/00046); the Spanish Ministry of Economy and Competitiveness (PTA2014-10228-I), and Fondo Europeo de Desarrollo Regional (FEDER 2007-2013). ProMPT: Founded by CRUK, NIHR, MRC, Cambride Biomedical Research Centre ProtecT: Founded by NIHR. ProtecT and ProMPT would like to acknowledge the support of The University of Cambridge, Cancer Research UK. Cancer Research UK grants (C8197/A10123) and (C8197/A10865) supported the genotyping team. We would also like to acknowledge the support of the National Institute for Health Research which funds the Cambridge Bio-medical Research Centre, Cambridge, UK. We would also like to acknowledge the support of the National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT) collaborative (grant code G0500966/75466) which has funded tissue and urine collections in Cambridge. We are grateful to staff at the Welcome Trust Clinical Research Facility, Addenbrooke&#39;s Clinical Research Centre, Cambridge, UK for their help in conducting the ProtecT study. We also acknowledge the support of the NIHR Cambridge Biomedical Research Centre, the DOH HTA (ProtecT grant), and the NCRI/MRC (ProMPT grant) for help with the bio-repository. The UK Department of Health funded the ProtecT study through the NIHR Health Technology Assessment Programme (projects 96/20/06, 96/20/99). The ProtecT trial and its linked ProMPT and CAP (Comparison Arm for ProtecT) studies are supported by Department of Health, England; Cancer Research UK grant number C522/A8649, Medical Research Council of England grant number G0500966, ID 75466, and The NCRI, UK. The epidemiological data for ProtecT were generated though funding from the Southwest National Health Service Research and Development. DNA extraction in ProtecT was supported by USA Dept of Defense award W81XWH-04-1-0280, Yorkshire Cancer Research and Cancer Research UK. The authors would like to acknowledge the contribution of all members of the ProtecT study research group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Department of Health of England. The bio-repository from ProtecT is supported by the NCRI (ProMPT) Prostate Cancer Collaborative and the Cambridge BMRC grant from NIHR. We thank the National Institute for Health Research, Hutchison Whampoa Limited, the Human Research Tissue Bank (Addenbrooke&#39;s Hospital), and Cancer Research UK. PROtEuS: PROtEuS was supported financially through grants from the Canadian Cancer Society (13149, 19500, 19864, 19865) and the Cancer Research Society, in partnership with the Minist&#232;re de l&#39;enseignement sup&#233;rieur, de la recherche, de la science et de la technologie du Qu&#233;bec, and the Fonds de la recherche du Qu&#233;bec - Sant&#233;.PROtEuS would like to thank its collaborators and research personnel, and the urologists involved in subjects recruitment. We also wish to acknowledge the special contribution made by Ann Hsing and Anand Chokkalingam to the conception of the genetic component of PROtEuS. QLD: The QLD research is supported by The National Health and Medical Research Council (NHMRC) Australia Project Grants (390130, 1009458) and NHMRC Career Development Fellowship and Cancer Australia PdCCRS funding to J Batra. The QLD team would like to acknowledge and sincerely thank the urologists, pathologists, data managers and patient participants who have generously and altruistically supported the QLD cohort. RAPPER: RAPPER is funded by Cancer Research UK (C1094/A11728; C1094/A18504) and Experimental Cancer Medicine Centre funding (C1467/A7286). The RAPPER group thank Rebecca Elliott for project management. SABOR: The SABOR research is supported by NIH/NCI Early Detection Research Network, grant U01 CA0866402-12. Also supported by the Cancer Center Support Grant to the Cancer Therapy and Research Center from the National Cancer Institute (US) P30 CA054174. SCCS: SCCS is funded by NIH grant R01 CA092447, and SCCS sample preparation was conducted at the Epidemiology Biospecimen Core Lab that is supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA68485). Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry, Lexington, KY; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry, 4815 W. Markham, Little Rock, AR 72205. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. SCPCS: SCPCS is funded by CDC grant S1135-19/19, and SCPCS sample preparation was conducted at the Epidemiology Biospecimen Core Lab that is supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA68485). SEARCH: SEARCH is funded by a program grant from Cancer Research UK (C490/A10124) and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. SNP_Prostate_Ghent: The study was supported by the National Cancer Plan, financed by the Federal Office of Health and Social Affairs, Belgium. SPAG: Wessex Medical ResearchHope for Guernsey, MUG, HSSD, MSG, Roger Allsopp STHM2: STHM2 was supported by grants from The Strategic Research Programme on Cancer (StratCan), Karolinska Institutet; the Linn&#233; Centre for Breast and Prostate Cancer (CRISP, number 70867901), Karolinska Institutet; The Swedish Research Council (number K2010-70X-20430-04-3) and The Swedish Cancer Society (numbers 11-0287 and 11-0624); Stiftelsen Johanna Hagstrand och Sigfrid Linn&#233;rs minne; Swedish Council for Working Life and Social Research (FAS), number 2012-0073STHM2 acknowledges the Karolinska University Laboratory, Aleris Medilab, Unilabs and the Regional Prostate Cancer Registry for performing analyses and help to retrieve data. Carin Cavalli-Bj&#246;rkman and Britt-Marie Hune for their enthusiastic work as research nurses. Astrid Bj&#246;rklund for skilful data management. We wish to thank the BBMRI.se biobank facility at Karolinska Institutet for biobank services. PCPT &#38; SELECT are funded by Public Health Service grants U10CA37429 and 5UM1CA182883 from the National Cancer Institute. SWOG and SELECT thank the site investigators and staff and, most importantly, the participants who donated their time to this trial. TAMPERE: The Tampere (Finland) study was supported by the Academy of Finland (251074), The Finnish Cancer Organisations, Sigrid Juselius Foundation, and the Competitive Research Funding of the Tampere University Hospital (X51003). The PSA screening samples were collected by the Finnish part of ERSPC (European Study of Screening for Prostate Cancer). TAMPERE would like to thank Riina Liikanen, Liisa Maeaettaenen and Kirsi Talala for their work on samples and databases. UGANDA: None reported UKGPCS: UKGPCS would also like to thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), The Orchid Cancer Appeal, The National Cancer Research Network UK, The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. UKGPCS should also like to acknowledge the NCRN nurses, data managers, and consultants for their work in the UKGPCS study. UKGPCS would like to thank all urologists and other persons involved in the planning, coordination, and data collection of the study. ULM: The Ulm group received funds from the German Cancer Aid (Deutsche Krebshilfe). WUGS/WUPCS: WUGS would like to thank the following for funding support: The Anthony DeNovi Fund, the Donald C. McGraw Foundation, and the St. Louis Men&#39;s Group Against Cancer.

  Study phs001391

• Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to the Antibody Drug Conjugate Sacituzumab Govitecan

  Sacituzumab Govitecan (SG), a novel antibody drug conjugate (ADC) incorporating the anti-TROP2 antibody hRS7 conjugated to a topoisomerase-1 inhibitor (SN-38) payload, is the first ADC to be approved for advanced triple negative breast cancer (TNBC). However, mechanisms governing therapeutic resistance to SG are not known. We sought to identify mechanisms of de novo and acquired resistance to SG through unbiased whole-exome sequencing (WES) and RNA sequencing analysis of pre-treatment and multi-site post-progression (autopsy) tumor specimens. We examined three metastatic TNBC cases exhibiting (1) de novo progression, (2) stable disease, and (3) a deep response followed by progression, then mapped the temporal and spatial genomic evolution of acquired resistance in the responding patient. We then conducted additional pre-clinical experiments to validate the observed resistance mechanisms. TROP2 RNA and gene copy number were associated with de novo resistance, as case (1) was found to have absent TROP2 expression in all specimens, case (2) expressed TROP2, while case (3) exhibited both expression and focal genomic amplification of the TACSTD2/TROP2 locus. The genomic phylogeny tree inferred from case (3) post-progression specimens revealed one branch harboring an acquired canonical E418K resistance mutation in TOP1 (encoding topoisomerase 1) and a subsequent sub-clonal TOP1 inactivating frameshift mutation, while a distinct branch exhibited acquisition of a novel T256R missense mutation in TACSTD2 (encoding TROP2). Both the TOP1- and TACSTD2-mutant clones seeded multiple distinct metastatic sites. Through reconstitution experiments in TROP2 negative cells we found that TROP2 T256R is a stable protein with defective cell membrane localization and reduced cell surface binding by RS7 compared to wild-type TROP2. Collectively, these findings underscore TROP2 as a determinant of initial response to SG, and they reveal parallel and mutually exclusive polyclonal molecular mechanisms of acquired resistance involving the direct antibody target and drug payload target in distinct metastatic subclones of a single patient. While further research is needed to extend these novel findings, this study highlights the specificity of SG and illustrates how identifying such mechanisms will inform rational therapeutic strategies to overcome ADC resistance.&nbsp;&nbsp;

  Study phs002555

• Neoadjuvant nivolumab or nivolumab plus ipilimumab in early-stage triple negative breast cancer: phase 2 adaptive BELLINI trial. WES

  The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary endpoint: two-fold increase in CD8+ T cells or IFNG), providing rationale for neoadjuvant ICI without chemotherapy. In window of opportunity cohorts A (4 weeks anti-PD1) and B (4 weeks anti-PD1 + anti-CTLA4), we observed immune activation in 53% (8/15) and 60% (9/15) of patients, respectively. High tumor-infiltrating lymphocytes (TILs) correlated with response. Based on these data, we opened cohort C for patients with high TILs (≥50%) who received 6 weeks neoadjuvant anti-PD1 + anti-CTLA4 followed by surgery (primary endpoint: pathological complete response, pCR). 53% (8/15) of patients had major pathological response (< 10% viable tumor) at resection, with 33% (5/15) having pCR. All cohorts met Simon’s two-stage threshold for expansion to stage II. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early TNBC.

  Study EGAS50000000568

• Neoadjuvant nivolumab or nivolumab plus ipilimumab in early-stage triple negative breast cancer: phase 2 adaptive BELLINI trial. RNA-Seq

  The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary endpoint: two-fold increase in CD8+ T cells or IFNG), providing rationale for neoadjuvant ICI without chemotherapy. In window of opportunity cohorts A (4 weeks anti-PD1) and B (4 weeks anti-PD1 + anti-CTLA4), we observed immune activation in 53% (8/15) and 60% (9/15) of patients, respectively. High tumor-infiltrating lymphocytes (TILs) correlated with response. Based on these data, we opened cohort C for patients with high TILs (≥50%) who received 6 weeks neoadjuvant anti-PD1 + anti-CTLA4 followed by surgery (primary endpoint: pathological complete response, pCR). 53% (8/15) of patients had major pathological response (< 10% viable tumor) at resection, with 33% (5/15) having pCR. All cohorts met Simon’s two-stage threshold for expansion to stage II. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early TNBC.

  Study EGAS50000000567