Search Results - EGA European Genome-Phenome Archive

Targeted and exome sequencing data from 24 prostate cancer patients with somatic hypermutation

This dataset contains all available targeted and exome sequencing paired fastq files from our study, "Identification of hypermutation and defective mismatch repair in ctDNA from metastatic prostate cancer". Patient identifiers are denoted by the first three characters of the sample aliases (e.g. "P01"), and additional information is appended to reflect the panel used (targeted 73 gene panel: "PC", or whole-exome panel: "WXS"), and whether the sample represents cell-free DNA ("cfdna") or paired white-blood cell control ("wbc"). Several patients have multiple serial collections available, and these are denoted by the characters "C1, C2, C3," etc. All samples were sequenced using Illumina technology.

Dataset EGAD00001005474

Single cell RNA sequencing data in "Three-dimensional human alveolar stem cell culture models reveal infection response to SARS-CoV-2"

This dataset includes a total of 5 single cell RNA sequencing (scRNAseq) data of SARS-CoV-2 infected human alveolar stem cell culture models. Two scRNAseq data were obtained from SARS-CoV-2 infection with MOI of 1.0 (1 for control and 1 for infected case) and the other three were obtained from SARS-CoV-2 infection with MOI of 0.1 in the study entitled "Three-dimensional human alveolar stem cell culture models reveal infection response to SARS-CoV-2". The 10x Chromium Single Cell 3' Reagent kits were used to generate libraries.

Dataset EGAD00001006242

TS and WGS data

The dataset contains the targeted sequencing (TS) and the whole genome low pass (WGS) BAM files of the study. For the TS: Samples: TS_XXX There are normal and tumor DNA samples. Each DNA strand has been sequenced independently (PoolA and PoolB). A TruSeq Custom Amplicon panel of 20 genes frequently mutated in ILC and/or ER-positive BC in general was designed using DesignStudio from Illumina: AKT1, ARID1A, CDH1, ERBB2, ERBB3, ESR1, FOXA1, GATA3, IGF1R, JAK2, MAP2K4, MAP3K1, NF1, PIK3CA, PTEN, RB1, RUNX1, STAT3, TBX3, and, TP53. For the WGS: Samples: WGS_XXX There are normal and tumor DNA samples. Samples were sequenced to an average target coverage of 0.5X.

Dataset EGAD00001006393

Dichotomous regulation of lysosomes by MYC and TFEB controls hematopoietic stem cell fate

We show that lysosomes are antagonistically controlled by TFEB and MYC to balance catabolic and anabolic processes required for activating LT-HSC and guiding their lineage fate. TFEB-mediated induction of the endolysosomal pathway for membrane receptor degradation limits LT-HSC metabolic and mitogenic activation; this promotes quiescence and self-renewal and governs erythroid-myeloid commitment. By contrast, MYC engages biosynthetic processes while repressing lysosomal catabolism to drive LT-HSC activation. Collectively, our study identifies lysosomes as a central regulatory hub for proper and coordinated stem cell fate determination.

Dataset EGAD00001006884

Summary Statistics GWAS SSNS

Column 1 “rsid”: SNP identifier Column 2 “chromosome”: name of chromosome on which the SNP is located Column 3: “position”: base pair position on the chromosome Column 4 “minor_test_allele”: the base that constitutes the minor allele Column 5 “major_allele”: the base that constitutes the major allele Column 6 “maf”: the frequency of the minor allele, indicated as a fraction of 1 Column 7 “allele_freq_cases”: the minor allele frequency in cases Column 8 “allele_freq_controls”: the minor allele frequency in controls Column 9 “regression_pvalue”: the p-value for the difference in allele frequency between cases and controls Column 10 “odds_ratio”: the odds ratio, as calculated using logistic regression under an additive model with adjustment for the first ten principal components of ancestry

Dataset EGAD00001008782

Whole-exome sequencing of glioblastomas with long-term relapse interval

Whole-exome sequencing data (Agilent SureSelectXT Human All Exon V7). Retrospective study of matched pairs of initial and post-therapeutic GBM cases treated with temozolomide+radiotherapy with a recurrence period greater than one year. Matched normal, initial and post-therapeutic samples for 27 patients and 1 patient (GBM046) with a matched normal and two post-therapeutic samples.

Dataset EGAD00001008568

Genomic signatures define three subtypes of EGFR-mutant stage II-III non-small-cell lung cancer with distinct adjuvant therapy outcomes

This dataset contains targeted sequencing data of 204 surgical samples from resected NSCLC. Genomic profiling identifies five predictive biomarkers, which is then integrated into the Multiple-gene INdex to Evaluate the Relative benefit of Various Adjuvant therapies (MINERVA) score. The MINERVA score categorizes patients into three subgroups with relative disease-free survival and overall survival benefits from either adjuvant gefitinib or chemotherapy. This study demonstrates that predictive genomic signatures could potentially stratify resected EGFR-mutant NSCLC patients and provide precise guidance towards future personalized adjuvant therapy.

Dataset EGAD00001008157

Mutation and Microsatellite Burden Predict Response to PD-1 Inhibition in Children with Germline DNA Replication Repair Deficiency: An Observational Registry Study

This dataset contains raw data from polyA RNAseq, hybrid capture target TCR panel data, and bam files from whole exome sequencing on 39 tumors with matched germline blood.

Dataset EGAD00001008036

Induction Failure in Childhood and Young Adult T-cell Acute Lymphoblastic Leukemia

We carried out WGS and RNAseq on a cohort of 48 children and young adults with induction failure in T-cell Acute Lymphoblastic Leukemia (T-ALL) to identify genomic drivers of treatment resistance. The study includes WGS for 33 tumour/normal pairs and 15 tumour-only samples. In addition, there is RNAseq data for 37 cases.

Dataset EGAD00001009058

Single-cell RNA sequencing of breast cancer lung metastasis and adjacent normal tissue

This dataset contains single-cell RNA sequencing data from two samples: L1 (breast cancer metastasis to lung) and N3 (adjacent normal lung tissue) from a female patient. The samples were processed using 10X Chromium 3' technology and sequenced on Illumina NextSeq 500. This data supports the study "Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via upregulation of P-Rex1/Rac1 signalling" which investigates how endocrine therapy reprograms breast cancer cells, leading to upregulation of P-Rex1/Rac1 signalling pathways that facilitate metastatic escape. The single-cell analysis reveals cellular reprogramming mechanisms in endocrine therapy-resistant breast cancer cells that form metastases in the lung.

Dataset EGAD00001015769

LCM_WES__Thyroid_

Whole exome sequencing through the low-input DNA pipeline in thyroid samples. Tissue will be processed either from laser capture microdissection or directly from bulk frozen/fixed/paraffin-embedded tissue. Insights will be gained here directly from the sequencing but also from using the data as a matched normal in Exome Nanoseq. Thyroid samples will be obtained from patients with and without thyroid disease.

Study EGAS00001007772

IFNγ Drives Long-Term Bone Marrow Niche Dysfunction Following Doxorubicin-Based Chemotherapy

To understand the impact of chemotherapy treatment on the bone marrow microenvironment, we acquired paired bone marrow (BM) aspirate samples from patients with acute lymphoblastic leukemia (ALL) collected at diagnosis and 4w later (end of induction therapy) at the Princess Margaret Hospital. The BM stroma was obtained by expanding BM aspirates in culture, and profiled by RNA-sequencing.

Study EGAS50000001621

Genetic Study of Vascular Anomalies

Vascular anomalies are malformations or tumors of the vasculature that can result in significant morbidity and mortality. Vascular anomalies are caused by germline or post-zygotic pathogenic variants in genes that regulate cell growth and vascular development. Complex or extensive vascular anomalies are often intractable despite interventions such as sclerotherapy, embolization, or surgery. In recent years, targeted therapy has played an increasingly crucial role in the management of these diseases. Identification of the molecular causes of vascular anomalies is essential to provide efficacious therapy; however, genetic profiling is often limited by difficulty obtaining affected tissues and limited sequencing depth. The lack of this information limits treatment options and the precision of targeted therapy, especially for primary complex lymphatic anomalies. To address these limitations, we have applied novel techniques, including analysis of unconventional samples such as endothelial cells isolated from lymphatic fluid and cell-free DNA, deep coverage exome sequencing, and unique molecular identifier ultra-deep targeted sequencing, in the molecular profiling of these diseases.

Study phs003197

National Institute of Environmental Health (NIEHS) Sciences Study of Somatic Mutation Load in Clones of Single Human Cells

Accumulation of genetic changes with time and proliferation of cells is inevitable. We report here the genome-wide magnitude and spectra of mutations accrued in skin fibroblasts over the lifetime of healthy humans. We found that every cell contains at least one somatic chromosomal rearrangement and 600 - 13,000 base substitutions, similar to the median mutation load in human cancers. The mutation spectra and correlation of changes with epigenomic features also resemble many human cancers. Interestingly, the magnitude of ultraviolet light-characteristic mutations, representative of environmental mutagenesis, in sun-exposed skin was comparable to the number of mutations attributed to endogenous DNA damage estimated in unexposed cells. Our methodology allows delineating the precise contributions of environmental and endogenous factors to the accrual of genetic changes in the human body. This is fundamental to understanding the etiology, and improving the prognosis and prevention of cancers and other genetic diseases.

Study phs001182

A Phase III Randomized Study of Nivolumab Plus Ipilimumab Versus Nivolumab in Stage IV Squamous Cell Lung Cancer

Lung-MAP (S1400, NCT02785952) was a multicenter, open-label, phase III randomized clinical trial. The Lung-MAP-I substudy (S1400I) was conducted from December 2015 to April 2018, through the National Clinical Trials Network and led by the SWOG Cancer Research Network. The trial compared nivolumab plus ipilimumab (nivo+ipi) with nivolumab monotherapy (nivo) in patients with chemotherapy-pretreated, immunotherapy-naïve, advanced squamous non-small cell lung carcinoma (sqNSCLC). Two hundred fifty-two patients were randomly assigned to receive nivo+ipi (n = 125) or nivo (n = 127). The clinical efficacy endpoints were overall survival, progression free survival, duration of response, and best objective response by RECIST 1.1. Multi-omic translational analysis was performed in collaboration with the the CIMAC–Cancer Immunologic Data Commons (CIDC) Network using available tumor tissue samples and blood samples (n = 160) submitted for Lung-MAP screening and provided by the SWOG tissue bank.

Study phs003412

A Translational, Pharmacodynamic and Pharmacokinetic Phase IB Clinical Study of Everolimus in Resectable Non-Small Cell Lung Cancer

This phase IB clinical trial studied the pharmacodynamic changes induced by everolimus in patients with previously untreated, resectable non small cell lung cancer. Using a combination of in vivo and ex vivo assessments with FDG PET, immunohistochemistry and genomic assays, evidence of mTOR pathway perturbation was assessed in patients treated with everolimus, an allosteric mTOR inhibitor. Untreated patients served as controls for comparison. Key results from this work include a dose-dependent biologic effect of everolimus, signal of activity in RAS mutant tumors as well as near complete metabolic and pathologic response in a case of sarcomatoid lung cancer. These findings represent novel translational insights that can guide future development of mTOR inhibitors in lung cancer and other tumor types. Additionally, metabolic response and anatomic tumor shrinkage observed in a significant proportion of patients following a short of duration of therapy with everolimus suggests potential clinical utility of this agent in carefully-selected lung cancer patients.

Study phs000829

Bulk RNA sequencing of day 2 and day 7 biopsies from the tuberculin skin test in people with latent tuberculosis, and of day 2 biopsies from saline controls

We used the tuberculin skin test (TST) as human challenge model to study the temporal evolution of the immune response to Mycobacterium tuberculosis (Mtb) antigens in vivo. Study participants comprised healthy HIV seronegative adults, 18-60 years of age. Latent tuberculosis (TB) infection was defined as immune memory for Mtb-specific antigens identified by positive peripheral blood IFNg release assays, but no clinical or radiological evidence of active TB. Two units tuberculin each were injected intradermally into the contralateral forearms of participants. After 2 days (n=216) or 7 days (n=158), 3 mm skin punch biopsies were taken from the injection sites and processed for whole genome transcriptional profiling by bulk RNA sequencing. The time points reflect maximum clinical inflammation (day 2) and maximum T cell infiltration (day 7) of the TST. TST samples were compared to skin biopsies taken two days after control injection of saline in a separate group of individuals (n=33), comprising healthy volunteers as well as patients with active or latent TB, ranging from 18-75 years of age. This dataset includes 407 samples from 256 individuals (n=33 saline, n=223 with Day 2 and/or Day 7 TST). Skin biopsies were collected into RNAlater (Qiagen) for RNA extraction. Total RNA was obtained with the Precellys Evolution homogenizer (Bertin Instruments) and Qiagen RNeasy mini kit. RNA was subjected to DNase treatment to remove contaminating genomic DNA using a TURBO DNA-free kit (Ambion, Life Technologies). The KAPA mRNA HyperPrep Kit (Roche Diagnostics) was used to construct stranded mRNA-Seq libraries from up to 500 ng intact total RNA. Paired-end sequencing was performed on the Illumina Nextseq using the Nextseq 500/550 High Output 75 cycle kit (Illumina). Runs were demultiplexed using bcl2fastq by Illumina.

Dataset EGAD50000001208

Utility of ctDNA to support patient selection for early phase clinical trials: The TARGET Study

Next generation sequencing (NGS) of circulating tumour DNA (ctDNA) supports blood-based genomic profiling but is not routinely implemented in the clinic. TARGET is a molecular profiling programme with the primary aim to match patients to early phase clinical trials based on analysis of both somatic mutations and copy number alterations (CNA) across a 641 cancer-associated gene panel in a single ctDNA assay. For the first 100 TARGET patients, ctDNA data showed good concordance with matched tumour and results were turned round within a clinically acceptable timeframe for Molecular Tumour Board (MTB) review. When applying a 2.5% Variant Allele Frequency (VAF) threshold actionable mutations were identified in 41/100 patients, with 11 of these patients going onto a matched therapy. These data support the application of ctDNA in an early phase trial setting where broad genomic profiling of contemporaneous tumour material enhances patient stratification to novel therapies and provides a practical template for bringing blood-based analyses to the clinic.

Study EGAS00001003407

Sequence data for study: Mobilization of tissue-resident memory CD4+ T lymphocytes from bone marrow and their contribution to a systemic secondary immune reaction

Resident memory T lymphocytes (TRM) of epithelial tissues and the bone marrow protect their host tissue. To what extent these cells are mobilized and contribute to systemic immune reactions is less clear. Here we show that in secondary immune reactions to the measles-mumps-rubella (MMR) vaccine, CD4+ TRM are mobilized into the blood within 16 to 48 hours after immunization. This mobilization of TRM is cognate: TRM recognizing other antigens are not mobilized, unless they cross-react with the vaccine. We also demonstrate through methylome analyses that TRM are mobilized from the bone marrow. These mobilized cells make significant contribution to the systemic immune reaction, as evidenced by their T-cell receptor Vβ clonotypes represented among the newly generated circulating memory T-cells, 14 days after vaccination. Thus, TRM of the bone marrow confer not only local, but also systemic immune memory.

Study EGAS00001005475

Study of complex rearrangements and mutational signatures in neuroblastoma heterogeneous risk groups.

Neuroblastoma is a pediatric solid tumor characterized by strong clinical heterogeneity. Although certain complex genomic alterations, such as extrachromosomal DNA amplifications (ecDNA), are associated with adverse outcome and have been recurrently detected in neuroblastomas, the mutational processes involved in their generation remain largely unclear. By examining the topography of complex rearrangements along with mutational signatures derived from all variant classes, we identify previously unrecognized co-occurring mutational footprints, which we termed mutational scenarios. We demonstrate that clinical neuroblastoma heterogeneity is linked to differences in the processes driving these mutational scenarios. Whereas high-risk MYCN-amplified neuroblastoma genomes were characterized by signs of replication slippage and stress, homologous recombination-associated signatures defined high-risk non-MYCN-amplified patients. Non-high-risk neuroblastomas, on the other hand, were marked by footprints of chromosome missegregation and TOP1 mutational activity. This analysis provides a systematic perspective on the repertoire of mutational patterns that contribute to clinical neuroblastoma heterogeneity.

Study EGAS00001006983

MutWP5: CRUK Mutographs of Cancer: Cancer Mastectomy (Exome)(Novaseq)

Sequencing of LCM-derived microbiopsies from 40 women who underwent mastecomies due to breast cancer. LCM and sequencing will be conducted on both normal, unaffected breast, and, where possible, tumour tissue. Goal to assess the mutational burden, spectrum, and clonal dynamics within the tissue, and compare findings between the normal and associated cancer tissues. Whole-genome sequencing will be conducted on samples identified as promising from the initial targeted data. Results from this poriton of the study will be compared to women who had cosmetic breast reduction surgeries and those who are BRCA carriers. . This dataset contains all the data available for this study on 2023-03-08.

Dataset EGAD00001010117

Mult-omics Palbociclib Resistance Study in HR+/HER2– Metastatic Breast Cancer

Resistance to CDK4/6 inhibitors and endocrine therapy (ET) are common and poorly understood since they have been real game changer in patients with HR-positive and HER2-negative MBC. A comprehensive genomic and transcriptomic analysis of pre-treatment and post-treatment tumors from patients treated with palbociclib plus ET identified novel markers associated with poor prognosis such as genomic scar features caused by homologous repair deficiency (HRD), estrogen response signatures, and four unique prognostic clusters with distinct molecular features. Tumors with TP53 mutations co-occurring with a unique HRD-high cluster responded poorly. By comparing genomic and transciptomic profiles of paired samples, tumors were found to be further enriched in HRD genomic scars and many had switched to aggressive molecular subtypes. Furthermore, we identified high frequencies of acquired genomic alterations upon disease progression in RB1, ESR1, PTEN, and KMT2C. Our findings provide new insight into potential predictive biomarkers that could be targeted to overcome resistance. (NCT03401359)

Study EGAS00001005736

Resuscitation Outcomes Consortium (ROC) Prehospital Resuscitation on Helicopter Study (PROHS) (ROC-PROHS-BioLINCC)

Accessing Data: Please refer to the "Authorized Access" section below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP.Objective: To observe if patients with severe traumatic injuries evacuated to level 1 trauma centers on air ambulances who received prehospital red blood cells and/or plasma had decreased in-hospital mortality compared to patients who received only crystalloids.Background: Injury is the leading cause of death in adults and children between the ages of 1 and 44 years. However, approximately 40% of in-hospital deaths among injured patients involve massive truncal hemorrhage that is considered potentially salvageable. Multiple retrospective military and civilian studies have reported that transfusion involving blood component ratios approaching whole blood are associated with significant decreases in 24-hour and 30-day mortality among injured patients. Furthermore, prehospital transfusion (PHT) studies from military and civilian hospitals have shown that prehospital transfusion of plasma and red blood cells (RBCs) is not only feasible, but associated with improved coagulation status on arrival. Prehospital resuscitation practices in the US differ significantly in approach, with most systems using crystalloids while a few offer RBCs or a combination of plasma and RBCs. No large multicenter civilian studies have evaluated the use of prehospital plasma and RBCs in severely injured patients compared to crystalloids.Participants: A total of 25,118 trauma patients were admitted during the 10 month enrollment period to the nine participating centers, of which 2341 arrived by helicopter, and 1058 met the highest risk criteria. Of the high risk sub-set, 585 arrived on helicopters with blood products available and 473 patients arrived via helicopters without blood available. One hundred forty two patients (24%) of those transported on helicopters with blood products available actually received PHT and 916 patients did not.Design: PROHS was a multicenter, prospective pragmatic, observational study of prehospital resuscitation approaches. There were no study guidelines dictating resuscitation practice (i.e., use of blood products or end of resuscitation). Of the 9 participating Level I trauma centers, 5 had helicopter systems with plasma and/or RBCs while the other 4 had helicopter systems that used only crystalloid resuscitation. All patients arriving to the participating center's trauma emergency department via helicopter directly from the scene were screened and had initial data collected. Of that group, all patients who met the highest risk category or received blood during transport were followed by direct observation during the initial resuscitation period and then indirectly through medical chart review until hospital discharge or 30 days after admission (whichever occurred first).The primary outcome was in-hospital mortality at 3 hours, 24 hours, and 30 days. Other outcome measures included length of hospital stay, number of ICU days, number of ventilator days, blood product usage, GOSE score at discharge, number of patients with complications, and number of patients who required hemostatic devices. Conclusions:Because of the unexpected imbalance in injury severity between systems with and without blood products on helicopters, all analyses were inconclusive. With few units transfused to each patient and small outcome differences between groups, large randomized studies will be required to detect significant survival differences in this important population.

Study phs003826

Innate Immune Anti-Viral Deaminase Deregulation Fuels Pre-Leukemia Stem Cell Evolution

This study evaluates the effect of Rebecsinib treatment on gene expression, isoform splicing, and ADAR1 mediated RNA editing in cells from an in vivo humanized mouse model which have been engrafted with human secondary AML cells. For analysis of cells from Rebesinib-treated animals, CD34+ cells were obtained from bone marrow and spleens of sAML-engrafted mice following once weekly treatment with 0 (Vehicle) or 5 or 10 mg/kg Rebecsinib. For analysis of cells from serial transplant recipients of cells harvested from Rebecsinib-treated mice, CD34+ cells were obtained from bone marrow and spleens of sAML-engrafted mice that were transplanted with cells from animals that received twice weekly treatment with 0 (Vehicle) or 10 mg/kg Rebecsinib. No further treatment was given to serial transplant recipients, thus allowing the analysis of molecular changes that are sustained following serial transplantation. Whole transcriptome sequencing was performed at The Scripps Research Institute Next Generation Sequencing Core on Illumina NextSeq 500 sequencers with 150bp paired-end reads.These data revealed a uniquely expressed ADAR1 splice isoform (with a retrained intronic region), global downregulation of normalized RNA editing events, and isoform switching from MCL1-L to MCL1-S in Rebecsinib-treated sAML-engrafted mice. These results demonstrate the anti-survival and anti-self-renewal effects of Rebecsinib treatment on the leukemia stem cell (LSC) population in sAML-engrafted mice as well as the reduction in the inflammation-induced, hyper-editing p150 isoform of ADAR1. Thus, Rebecsinib treatment has promise for reducing the LSC population in myeloproliferative disorders and associated cancers.

Study phs002228

Genetic Model of MS Severity Predicts Future Accumulation of Disability

The goal of "Comprehensive Multimodal Analysis of Neuroimmunological Diseases of the CNS" is to define the pathophysiological mechanisms underlying the development of disability in immune-mediated disorders of the central nervous system (CNS) and to distinguish these from physiological (and often beneficial) responses of the human immune system to CNS injury. The long-term objective of the trial is to acquire knowledge that would allow us to therapeutically inhibit the pathogenic mechanisms and enhance repair mechanisms in immune-mediated CNS diseases, thereby minimizing the extent of CNS tissue damage and promoting recovery. To date, 460 patients with a confirmed diagnosis of multiple sclerosis (MS) have been enrolled into the natural history clinical trial. In addition to standardized clinical, functional, neuroimaging and molecular/immunological data, blood samples were also collected for genetic research. However, only 299 study participants with confirmed MS currently have whole genome sequencing data available. In addition to the genome-wide data available for the 299 MS patients, this dbGaP submission provides demographic and phenotypic information for each subject collected at various points throughout the trial. We include race and family history of MS collected at the baseline visit as well as age and measures of disease severity collected at the most recent visit. As these data were randomized into discovery and validation cohorts, we also indicate the assigned group in the phenotypic data. It is hoped that these data may be applied to the development of clinically-useful tools such as diagnostic tests and new, sensitive scales of neurological disability, disease severity and CNS tissue destruction.

Study phs001833

Age related Macular Degeneration (AMD)-- Michigan, Mayo, AREDS, Pennsylvania (MMAP) Cohort Study: A Joint Genome Wide Association Study

Age-related Macular Degeneration (AMD) is a leading cause of incurable blindness in people over the age of 65. AMD is a late-onset multi-factorial neurodegenerative disease and its pathogenesis involves interaction of genetic and environmental factors. Several chromosomal regions have been associated with AMD susceptibility through linkage analysis (Swaroop et al., 2009). More recent studies provide strong evidence that variants within the CFH gene cluster on chromosome 1 and at/near LOC387715/ARMS2 on chromosome 10 are strongly associated with disease. Variants at other genes including C2/BF, C3, CFI and APOE4, also contribute to AMD susceptibility. Our primary goals are to identify genetic variants and haplotypes that are associated with AMD. The underlying hypothesis is that DNA variation(s) in multiple genetic susceptibility loci will predispose individuals to AMD pathogenesis, and comparison of DNA of cases and controls should identify these susceptibility variants. Our studies are focused on the genetic analysis of advanced AMD and should provide novel insights into disease diagnosis, progression and pathology. We have assembled a collaborative group of researchers from the University of Michigan, Mayo Clinic, University of Pennsylvania, and the AREDS group including National Eye Institute intramural investigators, who collected clinical data and DNA from a large number of patients affected with AMD and from unaffected controls. The primary source of funding was National Eye Institute. Through this collaborative effort, we submitted and obtained usable genotyping data on 2184 patients and 1155 controls from the Center for Inherited Disease Research (CIDR).

Study phs000182

Genetics of Prostate Cancer in Africa

African Americans (AA) suffer from the highest rates of Prostate Cancer (CaP) in the world, but while men of African descent around the world suffer disproportionately from CaP compared to men of other races or ethnicities, our understanding of the reasons for these disparities remains incomplete. To date, few exposure, lifestyle, or environmental influences have been identified in CaP etiology. In contrast, CaP is among the most heritable of common cancers, and over 290 susceptibility loci have been identified. However, many of these loci have not been replicated in AA, in part because of limited African descent sample sizes, incomplete capture of African alleles, and a limited understanding of African genomic architecture. To better understand the etiology of CaP in African descent men, we established a large, multicenter consortium known as “Men of African Descent and Carcinoma of the Prostate” (MADCaP). Using resources of this consortium, we have undertaken a multicenter study of CaP in Sub-Saharan Africa, enrolling CaP cases from 7 institutions in 4 countries in Africa (Nigeria, Senegal, Ghana, and South Africa) and age matched controls from the same institutions. We designed a novel genotyping array, in partnership with Thermo Fisher Scientific, leveraging its Applied BiosystemTM AxiomTM Genotyping solution, to provide good coverage of African genomic variation, as well as incorporating cancer loci, with the goal of being able to fine-map existing prostate cancer loci, as well as mapping novel loci. The data available encompasses genotyping our Africa cohort on this array.

Study phs002718

Clonally selected lines after CRISPR/Cas editing are not isogenic

The CRISPR-Cas9 system has enabled researchers to precisely modify/edit the sequence of a genome. A typical editing experiment consists of two steps: (i) editing cultured cells and (ii) selection of clones, which are presumed to be isogenic, with and without the intended edit. The application of the CRISPR-Cas9 system may result in off-target edits, while cloning would reveal culture-acquired mutations. We analyzed the extent of the former and of the latter by whole genome sequencing (WGS) involving separate genomic loci in three experiments conducted by three independent laboratories. In all experiments we hardly found any off-target edits, while we detected hundreds to thousands of single nucleotide mutations unique to each clone after relatively short culture of 10-20 passages. Notably, clones also differed in copy number alterations that were several kb to several mb in size, representing the largest source of genomic divergence among clones. This study in dbGaP includes data from experiments carried out by investigators at the Oklahoma Medical Research Foundation and Baylor College of Medicine (OMRF/BCM) involving an iPSC line derived from fibroblasts of a female patient (line c7) carrying a constitutional heterozygous variant (chr1:1,464,679 C>T; GRCh37) in exon 15 of the ATPase family, AAA domain containing 3A (ATAD3A) gene. The parental line was edited by introducing a double stranded break at the variant allele to correct the variant by homology directed repair. Two unedited control clones (clone7 and clone8) and one edited clone (SC20) were selected for WGS.

Study phs003110

Intra-tumor heterogeneity and clonal evolution of papillary renal cell carcinoma

Limited knowledge of intratumor heterogeneity (ITH), and clonal evolution of papillary renal cell carcinoma (pRCC) and rare kidney tumor subtypes hinders understanding of tumorigenesis and therapeutic efficacy. We conducted an integrative genomic and epigenomic ITH analysis and studied clonal evolutionary history of pRCC and rare kidney tumor subtypes. We dissected multiple consecutive samples from the center of the tumor towards the tumor's periphery, a normal sample ~5 cm distant from the tumor, and, where feasible, metastatic regions in the adrenal gland. Specifically, we performed 60X multi-region whole-genome sequencing (mWGS), both genome-wide methylation and SNP array profiling, and deep targeted sequencing (average 500X coverage) of 254 cancer driver genes (PMID:24390350). The study population comprises 39 patients with kidney cancers, including 23 with papillary type 1 (pRCC1), 12 with papillary type 2 (pRCC2), one of which also had areas of clear cell, and one each with collecting duct tumor (cdRCC), renal fibrosarcoma rSRC, mixed pRCC1/pRCC2, and an unclassified renal cancer with mixed features of pRCC2 and cdRCC. Based on DNA sample availability, we conducted whole genome sequencing (WGS) on 124 samples from 29 subjects, deep targeted sequencing on 139 samples from 38 subjects, SNP array genotyping on 101 samples from 38 subjects, and genome-wide methylation profiling on 139 samples from 28 subjects. All assays were performed on tumor, metastasis and normal tissue samples, with the exception of the SNP array genotyping, which was conducted only on tumor samples.

Study phs001573

High-Resolution Clonal Mapping of Multi-Organ Metastasis, and Resistance to Neoadjuvant Chemotherapy, in Triple Negative Breast Cancer

Clonal dynamics during metastasis were studied in two patient-derived xenograft (PDX) models established from treatment-naive primary breast tumors from TNBC patients diagnosed with concurrent metastatic disease. Genomic sequencing and barcode-mediated clonal tracking revealed robust alterations in clonal architecture between primary tumors and metastases. Polyclonal seeding and maintenance of low-abundance subclones was observed in each metastatic lesion examined. Lung, liver, and brain metastases were enriched for an identical population of subclones. Clones dominating multi-organ metastases shared a genomic lineage. Thus, properties of rare mammary tumor subclones enabled the seeding and colonization of metastases in multiple secondary organ sites. In this study, patient-derived xenograft (PDX) models of treatment-naive TNBC and serial biopsies from TNBC patients undergoing NACT were used to elucidate mechanisms of chemoresistance in the neoadjuvant setting. Barcode-mediated clonal tracking and genomic sequencing of PDX tumors revealed that residual tumors remaining after chemotherapy maintained the subclonal architecture of untreated tumors yet their transcriptomes, proteomes, and histologic features were distinct from those of untreated tumors. Once treatment was halted, residual tumors gave rise to chemotherapy-sensitive tumors with similar transcriptomes, proteomes, and histological features to those of untreated tumors. Taken together, these results demonstrated that tumors can adopt a reversible drug-tolerant state that does not involve clonal selection as a chemotherapy resistance mechanism. Serial biopsies obtained from patients with TNBC undergoing NACT revealed similar histologic changes as well as maintenance of stable subclonal architecture, demonstrating that PDXs capture molecular features characteristic of human TNBC chemoresistance.

Study phs001742

Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI)

(Excerpted/paraphrased from original grant application): FOCI seeks to expand our understanding of epithelial ovarian cancer through a coordinated and comprehensive approach. Project 1 will focus on discovery, expansion, and replication. By pooling GWAS, we expect to identify new associations and achieve independent replication, explore whether there are risk variants specific for histologic subtypes, and evaluate structural polymorphisms - copy number variants - as risk factors. Finally, Project 1 will leverage the GWAS data to correlate DNA variants with a new endpoint - survival. Project 2 will focus on biological studies designed to help inform interpretation of findings from Project 1. This will include efforts to identify the functional consequences of variants and improve understanding of biological mechanisms. Project 3 will include epidemiologic studies of gene by gene interaction, gene by environment interaction, and development of risk prediction models. The collective effort builds upon the strengths and history of collaboration inherent in the Ovarian Cancer Association Consortium (OCAC), a multidisciplinary group comprised of epidemiologists, genetic epidemiologists, statistical geneticists, molecular and cell biologists and clinicians that was formed in 2005. The FOCI Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs001133 FOCI Cohort. phs001131 Affymetrix Exome Chip phs001132 GWAS Meta Analysis phs001142 Mayo Omni Express phs001150 Mayo 2 5M

Study phs001133

Rare Diseases Clinical Research Network (RDCRN) Vasculitis Clinical Research Consortium (VCRC) Longitudinal Protocol for Polyarteritis Nodosa

The development and validation of accurate biological markers and predictors of disease activity and outcome in Polyarteritis Nodosa (PAN), a form a idiopathic vasculitis, would have a major positive impact on the clinical care of patients with this rare disease, be an important advance in the design of clinical trials and feasibility of new drug development, and provide important insight into the pathogenesis of this condition. Current measures of disease activity, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), while helpful in selected settings, are mostly considered highly flawed and markers whose poor correlation with disease flares makes them inadequate to help guide therapy. Similarly, ESR and CRP are clearly unhelpful as diagnostic tests for vasculitis. The current state of clinical investigation for vasculitis relies heavily upon determination of disease status solely by clinical presentation and investigator opinion. Thus, discovery and validation of more precise markers that quantifiably measure activity, predict disease course, and correlate with an important biological process, would be of great importance. Knowledge to be gained from this study could potentially be highly important. Discovery of effective biomarkers of vasculitis and assessment of long term disease course and complications by the collection of clinical and diagnostic imaging studies proposed could lead to better care and less toxic treatment regimens. Furthermore, insight into the pathophysiology of vasculitis could be gained and this might lead to better treatments and improved outcomes in terms of reduction of vascular and treatment related complications. Ideally, excellent biomarkers reflect a sophisticated understanding of the pathophysiology of a disease.

Study phs000590

Genetic Modifiers of Syndromic Orofacial Clefts

Reduced penetrance and variable expressivity are common, but poorly understood, features of most monogenic diseases. Genetic modifiers are possible factors to contribute to this phenotypic variability and blur the traditional distinction between monogenic and complex disease. This study focuses on the most common orofacial cleft syndrome (Van der Woude syndrome, VWS) and nonsyndromic orofacial clefts (OFCs), which intersect both in phenotype and in genetic etiology, as a model to understand reduced penetrance and variable expressivity. VWS occurs in 1 in 35,000 individuals and accounts for 2% of all OFCs. The features of VWS include an OFC and/or lower lip pits, but 15% of VWS patients present with an isolated OFC, making them indistinguishable from nonsyndromic OFC patients. Mutations in the genes IRF6 or GRHL3 cause VWS, but approximately 20% of VWS patients currently lack a molecular diagnosis. Furthermore, there are few genotype-phenotype correlations for known mutations and patient phenotypes. By contrast, GWAS of nonsyndromic OFCs have identified a number of risk factors, some of which we have shown increase risk for specific types of OFCs or act as modifiers of OFC subtypes. Whole genome sequencing will be used to identify the remaining genetic mutations for VWS, determine the relationship between those genes/regions with nonsyndromic OFCs, and identify rare and common modifiers of VWS and OFC phenotypes. These analyses will provide further insight into the genetic architecture of VWS and OFCs and will serve as a model for exploring links between other Mendelian disorders that share phenotypes with complex traits.

Study phs002221

Basal-to-Inflammatory Transition Contributes to Basal Cell Carcinoma Therapy Resistance via Crosstalk with a Pro-Inflammatory Stromal Niche

Overcoming tumor evolution and inducible resistance states remain the main challenge to creating successful anti-tumor therapies. The body's cancer-associated inflammatory response is a double-edged sword having ill-defined pro- and anti-tumor properties. Our group previously identified a basal cell carcinoma (BCC) tumor-intrinsic resistance pathway called basal to squamous cell carcinoma transition (BST). However, tumor resistance driven through the complex dynamics of tumor interactions with the inflammatory response remains poorly studied. Here, employing a multipronged approach combining human tumor single-cell transcriptomics, single-cell chromatin accessibility (scATAC-Seq) study, CODEX multiplexed imaging, spatial transcriptomic along with functional validation, we have identified a surprising inflammation-associated SMOi therapy enriched tumor epithelial cell state we term basal-to-inflammatory transition (BIT). Marked by CHI3L1, TAGLN, ITGAV, and VCAM1, BIT arises in spatially distinct neighborhoods from BST in a subset of naive BCCs. While BST tumor epithelium occurs within the central cores of tumor nodules, BIT tumor epithelium arises in a specialized inflammatory environment defined by a tumor associated TREM1 myeloid signature. IL1 and OSM secreted by TREM1 myeloid cells activate the inflammatory NF-kB family of transcription factors within the BIT tumor epithelium. Strikingly, IL1 and OSM ligands are sufficient not only in inducing the BIT tumor state in vitro and in vivo in a synergistic fashion but also in lowering the sensitivity of human BCC explant tumors to SMOi treatment. This work provides critical insights into the BIT-resistant state as a novel targetable tumor state driven by a specialized inflammatory microenvironment.

Study phs003437

Mayo Clinic - Fecal Microbiota and Adenomas

Background: Adenomatous polyps are the most common precursor to colorectal cancer (CRC), the second leading cause of cancer death in the United States. We sought to learn more about early events of carcinogenesis by investigating shifts in the gut microbiota of patients with adenomas. Methods: We analyzed 16S rRNA gene sequences from the fecal microbiota of patients with adenomas (n=233) and without (n=547). Results: Multiple taxa were significantly more abundant in patients with adenomas, including Bilophila, Desulfovibrio, pro-inflammatory bacteria in the genus Mogibacterium, and multiple Bacteroidetes species. Patients without adenomas had greater abundances of Veillonella, Firmicutes (Order Clostridia), and Actinobacteria (family Bifidobacteriales). Many of our findings were consistent with previously reported shifts in the gut microbiota of CRC patients. Importantly, the altered adenoma profile is predicted to increase primary and secondary bile acid production, as well as starch, sucrose, lipid, and phenylpropanoid metabolism. Conclusions: These data suggest that diets rich in refined sugar, protein, and lipids may lead to increased bile acid production, creating a colonic environment that promotes the growth of bile-tolerant microbes such as Bilophilia and Desulfovibrio. In turn, these microbes may produce genotoxic or inflammatory metabolites such as H2S and secondary bile acids, catalyzing adenoma development and eventually CRC. Impact: This study suggests a plausible biological mechanism to explain the links between diet, shifts in the microbiota, and CRC. This represents a first step toward resolving the complex interactions that shape the adenoma-carcinoma sequence of CRC and may facilitate personalized therapeutics focused on the microbiota.

Study phs001204

Digitalis Investigation Group (DIG-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 To determine the effect of increasing age on mortality, hospitalizations, and digoxin side effects in patients with heart failure (HF), and to determine whether the effect of digoxin on clinical outcomes varies as a function of age. Background The incidence and prevalence of HF increase with advancing age, but there are limited data on the clinical course and response to specific interventions in elderly patients with HF. Participants A total of 302 centers in the United States and Canada enrolled 7,788 patients between February 1991 and September 1993. Design The Digitalis Investigation Group (DIG) study was a prospective, randomized clinical trial involving 7,788 patients with HF randomized to digoxin or placebo and followed for an average of 37 months. Interactions between age and the following clinical outcomes were examined: total mortality, all-cause hospitalizations, HF hospitalizations, the composite of HF death or HF hospitalizations, hospitalization for suspected digoxin toxicity and withdrawal from therapy because of side effects. Conclusions Increasing age is associated with progressively worse clinical outcomes in patients with HF. However, the beneficial effects of digoxin in reducing all-cause admissions, HF admissions, and HF death or hospitalization are independent of age. Thus, digoxin remains a useful agent to the adjunctive treatment of HF due to impaired left ventricular systolic function in patients of all ages.

Study phs003872

Colon Cancer Family Registry (Colon CFR)

The Colon Cancer Family Registry Cohort (CCFRC www.coloncfr.org) is a cohort of families recruited through six study sites located in the USA, Canada, Australia, and New Zealand. The CCFRC was formed as a resource to support studies on the etiology, prevention, and clinical management of colorectal cancer. Recruitment protocols fall broadly into two main categories: population-based and clinic-based ascertainment. Between 1998 and 2013, the CCFR recruited and interviewed probands who were either recently diagnosed with colorectal cancer that was reported to state or regional population cancer registries in the United States (Washington, California, Arizona, Minnesota, Colorado, New Hampshire, North Carolina, and Hawaii), Australia (Victoria), and Canada (Ontario) or were from multiple-case families referred to family-cancer clinics in the United States (Mayo Clinic in Rochester, Minnesota, and Cleveland Clinic in Cleveland, Ohio), Australia (Melbourne, Adelaide, Perth, Brisbane, and Sydney), New Zealand (Auckland), and Canada. Cases with known familial adenomatous polyposis were excluded. Once recruited, probands were asked for permission to contact their relatives for recruitment. Collectively, we have enrolled 42,49874 participants in 15,048 families who participated in standardized protocols used to collect information regarding family cancer history and colorectal cancer risk factors and biospecimens. All participants of population-based case families (excluding control-families) and clinic-based families are asked to provide updates on their personal and family history of cancer as well as their history of surgery, cancer screening, and some risk factors every 4-5 years either by telephone interview or by self-completed questionnaire via mail or online (PMID: 17982118).

Study phs002733

Women's Ischemia Syndrome Evaluation (WISE-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: This is a National Heart, Lung and Blood Institute sponsored, four-center study designed to: 1) optimize symptom evaluation and diagnostic testing for ischemic heart disease; 2) explore mechanisms for symptoms and myocardial ischemia in the absence of epicardial coronary artery stenoses, and 3) evaluate the influence of reproductive hormones on symptoms and diagnostic test response.Background: Women tend to have a higher prevalence of chest pain than men, yet a lower prevalence of epicardial coronary stenoses, and diagnostic tests such as exercise-induced ECG changes tend to have a higher false-positive rate in women than in men. Thus, accurate diagnosis of ischemic heart disease in women is a major challenge to physicians. In addition, prognosis in women with abnormal diagnostic tests is largely unknown and the role reproductive hormones play in this diagnostic uncertainty is unexplored. Moreover, the significance and pathophysiology of ischemia in the absence of significant epicardial coronary stenoses is unknown.Participants: In Phase I (1996-1997), a pilot phase, 256 women were studied. During Phase II (1997-1999) angiographic and baseline data were collected on an additional 680 women to bring total enrollment to 936. Baseline data was also collected on a reference population of 70 women.Conclusions: Among women without CAD, abnormal Magnetic Resonance Spectroscopy (MRS) consistent with myocardial ischemia predicted cardiovascular outcome, notably higher rates of anginal hospitalization, repeat catherization, and greater treatment costs.

Study phs004310

Target sequencing of 27 cancer-predisposing genes in Japanese colorectal cancer patients

Background: National Comprehensive Cancer Network (NCCN) recently recommended germline genetic testing for all pancreatic cancer patients. However, the genes targeted by genetic testing and the feasibility of selecting patients likely to carry pathogenic variants have not been sufficiently verified. The purpose of this study was to genetically characterize Japanese patients and examine whether the current guideline is applicable in this population. Methods: Using targeted sequencing, we analyzed the coding regions of 27 cancer-predisposing genes in 1,005 pancreatic cancer patients and 23,705 controls in Japan. We compared the pathogenic variant frequency between cases and controls and documented the demographic and clinical characteristics of carrier patients. We then examined if it was possible to use machine learning to predict carrier status based on those characteristics. Findings: We identified 205 pathogenic variants across the 27 genes. Pathogenic variants in BRCA2, ATM, and BRCA1 were significantly associated with pancreatic cancer. Characteristics associated with carrier status were inconsistent with previous investigations. Machine learning classifiers had a low performance in determining the carrier status of pancreatic cancer patients, while the same classifiers, when applied to breast cancer data as a positive control, had a higher performance that was comparable to that of the NCCN guideline. Interpretation: Our findings support the clinical significance of multigene panel testing for pancreatic cancer and indicate that at least 3.4% of Japanese patients may respond to poly (ADP ribose) polymerase inhibitor treatments. The difficulty in predicting carrier status suggests that offering germline genetic testing for all pancreatic cancer patients is reasonable.

Study JGAS000346

Target sequencing of 27 cancer-predisposing genes in Japanese pancreatic cancer patients

Background: National Comprehensive Cancer Network (NCCN) recently recommended germline genetic testing for all pancreatic cancer patients. However, the genes targeted by genetic testing and the feasibility of selecting patients likely to carry pathogenic variants have not been sufficiently verified. The purpose of this study was to genetically characterize Japanese patients and examine whether the current guideline is applicable in this population. Methods: Using targeted sequencing, we analyzed the coding regions of 27 cancer-predisposing genes in 1,005 pancreatic cancer patients and 23,705 controls in Japan. We compared the pathogenic variant frequency between cases and controls and documented the demographic and clinical characteristics of carrier patients. We then examined if it was possible to use machine learning to predict carrier status based on those characteristics. Findings: We identified 205 pathogenic variants across the 27 genes. Pathogenic variants in BRCA2, ATM, and BRCA1 were significantly associated with pancreatic cancer. Characteristics associated with carrier status were inconsistent with previous investigations. Machine learning classifiers had a low performance in determining the carrier status of pancreatic cancer patients, while the same classifiers, when applied to breast cancer data as a positive control, had a higher performance that was comparable to that of the NCCN guideline. Interpretation: Our findings support the clinical significance of multigene panel testing for pancreatic cancer and indicate that at least 3.4% of Japanese patients may respond to poly (ADP ribose) polymerase inhibitor treatments. The difficulty in predicting carrier status suggests that offering germline genetic testing for all pancreatic cancer patients is reasonable.

Study JGAS000327

Sequencing and analysis of a South Asian-Indian personal genome

India with over 1.3 billion people is estimated to carry three times more genetic diversity compared to Europe. Next-generation sequencing technologies have facilitated the understanding of diversity by enabling whole genome sequencing at greater speed and lower cost. While multiple genomes from people of European and a few of Asian descent have been sequenced, only recently a single male genome from the Indian subcontinent at sufficient depth and coverage was published. We have in this study sequenced and analyzed the genome of a South Asian Indian female (SAIF) from the Indian state of Kerala. We identified over 3.4 million SNPs in this genome including over 89,873 private variations. Comparison of the SAIF genome with several published personal genomes revealed that this individual shared ~50% of the SNPs with each of these genomes. Analysis of the SAIF mitochondrial genome showed that it is closely related to the U1a3 haplogroup which has been previously observed in Kerala. We assessed the SAIF genome for SNPs with health and disease consequences and found that the individual was at a higher risk for multiple sclerosis and a few other diseases. In assessing SNPs that modulate drug response we found a variation that predicts a favorable response to metformin used for treating diabetes. SNPs predictive of adverse reaction to warfarin indicated that the SAIF individual is not at risk for bleeding if treated with typical doses of warfarin. In addition to these, we report the presence of several other SNPs of medical relevance.

Study EGAS00001000328

Impact of Glycolysis Inhibition on the Epigenome of Synovial Fluid T Cells in Juvenile Idiopathic Arthritis

Juvenile Idiopathic Arthritis (JIA) encompasses a group of childhood-onset autoimmune conditions characterized by joint inflammation and mononuclear cell infiltration, especially of activated CD4+ memory/effector T (Tmem/Teff) cells in synovial fluid (SF). JIA CD4+ T cells exhibit a distinct inflammation-associated epigenomic profile, though the underlying molecular mechanisms remain unclear. This study investigates the role of glycolysis in shaping the epigenomic landscape of JIA SF CD4+ T cells, with a focus on H3K27ac histone modifications. Using an ex vivo model of antigen stimulation, CD4+ T cells were isolated from peripheral blood (PB) of healthy controls (HC) and synovial fluid from JIA patients. Cells were activated in vitro with anti-CD3/CD28 for 24 hours, and changes in H3K27ac were assessed by chromatin immunoprecipitation followed by sequencing (ChIP-seq). To explore the specific role of glycolysis, cells were also treated with 2-deoxyglucose (2DG), an inhibitor of glucose-6-phosphate production. This inhibition impacted both H3K27ac acetylation patterns and gene expression associated with the activated epigenomic regions. Additionally, HC CD4+ T cells were activated in vitro in the presence of 30% SF or 30% plasma from JIA patients. RNA sequencing (RNA-seq) was performed to examine SF-induced transcriptional changes, providing insight into the metabolic dysregulation and epigenomic alterations observed in JIA SF CD4+ T cells. This dataset includes ChIP-seq and RNA-seq data that collectively advance our understanding of how glycolysis and the SF environment contribute to the epigenetic and transcriptional regulation in JIA CD4+ T cells.

Study EGAS50000000808

Tremelimumab +/- durvalumab in combination with paclitaxel as immune induction in metastatic urothelial cancer: clinical and translational results of the ICRA trial

DESCRIPTION: New therapeutic strategies for therapy-refractory metastatic urothelial carcinoma (mUC) patients are still needed. In the phase I-II ICRA trial, we evaluated whether paclitaxel plus tremelimumab (T; anti-CTLA-4), with or without durvalumab (D; anti-PD-L1), could induce a tumor response in mUC patients who had already received platinum chemotherapy and immune checkpoint inhibition (ICI). After a dose-escalation safety phase, patients were randomized between three arms: A (n=20 after expansion) paclitaxel plus T750mg (cycles 2-8); B (n=12) paclitaxel plus T300mg (cycle 2) plus D1500mg (cycles 2-13); C (n=12) T750mg (cycles 1-7). The objective response rate in arm A was 26% (88% confidence interval (CI) = [14,36%]) versus 17% (88% CI = [3,42%]) in arm B and 8% (88% CI = [0.3,33%]) in arm C. Grade 3-4 treatment-related adverse events occurred in (A) 45%, (B) 75%, and (C) 25% of patients. Murine experiments showed attenuated tumor outgrowth for paclitaxel plus anti-CTLA-4 compared to monotherapy with either agent. Transcriptomic analyses showed upregulation of inflammation signatures in on-treatment tumor tissue biopsies. This study demonstrated encouraging antitumor activity in therapy-refractory mUC treated with paclitaxel plus high-dose anti-CTLA-4 and suggests immune induction may still be possible after failure to anti-PD-(L)1 therapy. PROJECT GOAL: We aimed to explore both potential biomarkers for response to combination ICB, as well as treatment dynamics to gain a better understanding of the effects of ICB on the urothelial cancer tumor microenvironment (TME).

Study EGAS50000001574

Surgery in combination with immune checkpoint therapy as an effective treatment for patients with metastatic cancer.

Abstract Surgical removal of primary tumors was shown to reverse tumor-mediated immune suppression in pre-clinical models with metastatic disease. However, how cytoreductive surgery in the metastatic setting modulates the immune responses in patients, especially in the context of immune checkpoint therapy (ICT)-containing treatments is not understood. Here, we report the first prospective, non-comparative clinical trial (N=104) using three different ICT-containing strategies plus cytoreductive or “debulking” surgery to remove the primary tumor-bearing kidney or a metastatic lesion as a treatment for patients (N=43) with metastatic clear cell renal cell carcinoma (mccRCC). For those patients (N=61) who were not candidates for cytoreductive surgery, a biopsy was obtained instead for correlative biological studies. Our data demonstrated that the combination of ICT with cytoreductive surgery was safe and feasible in patients with mccRCC. The 2-year overall survival was 84% with a median OS of 54.7 months for patients who received ICT containing regimens plus surgery. Immune-monitoring studies with co-detection by indexing (CODEX) identified distinct tumor spatial conformation of cellular subsets as a novel and improved predictor of response to ICT. Importantly, single-cell RNA-sequencing data demonstrated that surgical removal of the tumor increased antigen-presenting dendritic cell population with a concurrent reduction in KDM6B expressing immune-suppressive myeloid cells in the peripheral blood. Together, this study highlighted the feasibility of combining ICT with cytoreductive surgery in a metastatic setting and demonstrated potential enhancement of immune responses following ICT plus cytoreductive surgery in patients with metastatic disease.

Study EGAS00001005667

Uncovering the potential of circulating tumor DNA for pediatric precision oncology

Pediatric solid high-risk malignancies mostly lack molecular biomarkers for early tumor detection, assessment of minimal residual disease or therapy monitoring. Small patient numbers, limited sample volumes, low tumor mutational burden, and few recurrent alterations in pediatric tumors pose further challenges to liquid biopsy analyses for this patient population. Within the prospective, multinational molecular profiling program INFORM, we collected liquid biopsies from 130 children patients followed by optimized isolation of cell-free DNA (cfDNA). CfDNA was subjected to whole-genome, whole-exome, and targeted panel sequencing applying liquid biopsy-adapted protocols. Integration with tissue-derived molecular information and orthogonal comparison revealed low-coverage whole genome sequencing (lcWGS) as a reliable method for tumor detection. In silico integration of fragment length with differentially weighted genome segment alterations into a ctDNA estimation score (CES) significantly increased sensitivity and specificity to 95% and allowed for plasma-based tumor detection in 93% of patients. Performance of whole exome sequencing (WES) and panel sequencing for detection of molecular targets being predictive for matched treatment responses varied between groups of high-risk entities and cumulative evidence for presence of cancer by all three methods was found in 92% of patients. In-depth analyses for selected patients also demonstrated great the potential of liquid biopsies to decipher temporal and spatial tumor evolution. This study establishes improved methods for liquid biopsy analyses in pediatric oncology and provides the rationale for well-informed implementation of these approaches in future clinical trials to improve the clinical management of high-risk pediatric cancer patients.

Study EGAS50000000393

Nanopore sequencing of blood, saliva, buccal mucosa samples of patients with inherited retinal disorders

X-linked genetic disorders typically affect females less severely than males due to the presence of a second X chromosome not carrying the deleterious variant. However, the phenotypic expression in females is highly variable, which may be explained by an allelic skew in X chromosome inactivation. Accurate measurement of X inactivation skew is crucial to understand and predict disease phenotype in carrier females, with prediction especially relevant for degenerative conditions. We propose a novel approach using nanopore sequencing to quantify skewed X inactivation accurately. By phasing sequence variants and methylation patterns, this single assay reveals the disease variant, X inactivation skew, its directionality, and is applicable to all patients and X-linked variants. Enrichment of X-chromosome reads through adaptive sampling enhances cost-efficiency. Our study includes a cohort of 16 X-linked variant carrier females affected by two X-linked inherited retinal diseases: choroideremia and RPGR-associated retinitis pigmentosa. As retinal DNA cannot be readily obtained, we instead determine the skew from peripheral samples (blood, saliva and buccal mucosa), and correlate it to phenotypic outcomes. This revealed a strong correlation between X inactivation skew and disease presentation, confirming the value in performing this assay and its potential as a way to prioritise patients for early intervention, such as gene therapy currently in clinical trials for these conditions. Our method of assessing skewed X inactivation is applicable to all long-read genomic datasets, providing insights into disease risk and severity and aiding in the development of individualised strategies for X-linked variant carrier females.

Study EGAS50000000440

Tumor Evolution Analysis Uncovered Immune-Escape Related Mutations in Relapsed Diffuse Large B-Cell Lymphoma

More than 60% of patients with primary diffuse large B-cell lymphoma (DLBCL) achieve durable remissions upon the chemoimmunotherapy with R-CHOP. However, the outcome of the relapse patients is extremely poor. To characterize the molecular features that underlie treatment resistance, we performed whole-exome sequencing (n=44) and deep targeted sequencing (n=27) of 44 diagnosis-relapse DLBCL pairs. We found that the overall landscape of genetic alterations was concordant between diagnosis and relapse DLBCL. By a deep comparison of the longitudinal sequencings, we identified relapse-enriched mutations that involved in evasion of immune surveillance (CD58, TNFRSF14, PKD1, FAS), resistance to DNA damaging agents (ATM, TP53), and critical tumor suppressor gene (ZFHX3). Knockdown of ATM and ZFHX3 resulted in increased drug resistance in both germinal center B cell like (GCB) and activated B cell like (ABC) DLBCL cell lines in vitro, while the knockdown of TNFRSF14 and FAS conferred resistance specifically in GCB cell lines. Furthermore, we summarized two evolutionary patterns of DLBCL relapse as the “durable retention” model with stable clone structure, and the “selective sweep” model which exhibited significant clonal switch. Of note, genetic alterations leading to attenuated immune responses usually presented as trunk mutations in the “durable retention” model (7/12) while were newly acquired or expanded upon relapse in the “selective sweep” model (9/16). Overall, our study demonstrated that relapse DLBCL derives from distinct clonal evolutionary patterns, and highlighted immune escape as an important contributor of tumor relapse.

Study EGAS50000000032

Oncogenic fate conversion by PRDM16s causes acute myeloid leukemia

Oncogenic mutations confer aberrant replicative capacity to cells with little or no replicative capacity, generating cancer stem cells that perpetuate the tumor through extensive self-replication and differentiation blockade. However, whether oncogenes disrupt the cellular identity ofcancer stem cell by altering the developmental potential is unknown. Fate conversion has been demonstrated by ectopic expression of master transcriptional regulators, such as PU.1 and C/EBP alpha that confers myeloid cell fate to other cell types, and PRDM16 that confers brown adipose fate to white adipocytes or myoblasts. Here we show that a transcriptional regulator overexpressed in human myeloid malignancies, PRDM16s, causes oncogenic fate conversion, by transforming cells fated to form platelets and erythrocytes into myeloid leukemia-initiating cells (LICs). Prdm16s expression in hematopoietic progenitor cells caused a myelodysplastic syndrome (MDS)-like disease that progressed to acute myelogenous leukemia (AML). The myeloid diseases caused by Prdm16s exhibited expansion of megakaryocyte-erythroid progenitors (MEPs) but not granulocyte-macrophage progenitors. MEPs from Prdm16s-induced leukemia possessed LIC potential, and expression of Prdm16s in normal MEPs was sufficient to convert them to myeloid LICs and blocked megakaryocytic/erythroid potential. Prdm16s induced the expression of myeloid master regulators, including PU.1 and C/EBP alpha, by interacting with their super enhancers. Ablation of myeloid master regulators attenuated the myeloid potential and reinstalled the megakaryocytic/erythroid potential of leukemic-MEPs in mouse models and in human AML with PRDM16 rearrangement. Our study demonstrates that oncogenic Prdm16 expression converts the fate of MEPs to a malignant myeloid fate by activating myeloid master transcription factors.

Study EGAS00001003235

Neoadjuvant immunotherapy leads to pathological responses in MMR proficient and MMR deficient early stage colon cancers

PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab + nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86–100%) dMMR tumors, with 19 major pathological responses (MPRs, ≤10% residual viable tumor) and 12 pathological complete responses. In pMMR tumors, 4/15 (27%; 95% exact CI: 8–55%) showed pathological responses, with 3 MPRs and 1 partial response. CD8+PD-1+ T cell infiltration was predictive of response in pMMR tumors. These data indicate that neoadjuvant immunotherapy may have the potential to become the standard of care for a defined group of colon cancer patients when validated in larger studies with at least 3 years of disease-free survival data.

Study EGAS00001004160

Search for new loci and low-frequency variants influencing glioma risk by exome-array analysis

To identify protein altering variants (PAVs) for glioma we analysed Illumina HumanExome BeadChip exome array data on 1,882 glioma cases and 8,079 controls from three independent European populations. In addition to single variant tests we incorporated information on the predicted functional consequences of PAVs and analysed sets of genes with a higher likelihood of having a role in glioma on the basis of the profile of somatic mutations documented by large-scale sequencing initiatives. Globally tThere was a strong relationship between effect size and SNPs predicted to be damaging (P=2.29x10-49); however, these variants which are most likely to impact on risk, are rare (MAF<5%). While no single variant showed an association which was statistically significant at the genomewide threshold a number of represented promising Notable associations - were seen with the BRCA2:c.9976A>T, p.(Lys3326Ter)BRCA2 p.Lys332X variant, which has been shown documented to influence breast and lung cancer risks (OR=2.3, P=4.00x10-4 for glioblastoma [GBM]) and IDH2:c.782G>A, p.(Arg261His)IDH2 p.Arg261His (OR=3.21, P=7.67x10-3, for non-GBM). Additionally, gene burden tests revealed a statistically significant association for HARS2 and risk of GBM (P=2.20x10-6). Genome scans of low frequency PAVs represent a complementary strategy to identify disease-causing variants compared with scans based on tagSNPs. Strategies to lessen the multiple testing burden by restricting analysis to PAVs with higher priors affords an opportunity to maximise study power.

Study EGAS00001001258

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