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• Developing Targeted Therapy for Patients with Multiple Myeloma and Gain or Amplification of Chr1q (1q+)

  Multiple myeloma (MM) frequently presents with gain or amplification of chr1q (1q+), which is associated with inferior response to treatment and poor outcomes. To develop targeted therapy for MM with 1q+, we leveraged external and in-house dependency screens and drug screens, along with single-cell sequencing of patient tumors with subclonal 1q+. We demonstrated that MM with 1q+ exhibits higher sensitivity to MCL1 and PI3K inhibitors, which may be synergistic and act through established and novel mechanisms. Two human MM cell lines with 1q+, KMS12BM and KMS11, were profiled with either single-cell RNA-sequencing (scRNA-seq) alone (KMS12BM, KMS11) or both scRNA-seq and whole-genome sequencing (WGS; KMS12BM) to understand the factors that determine response to MCL1 and PI3K inhibitors and how these inhibitors work.

  Study phs003886

• NHLBI TOPMed - NHGRI CCDG: Intermountain INSPIRE Registry

  The INtermountain Healthcare Biological Samples Collection Project and Investigational REgistry for the On-going Study of Disease Origin, Progression and Treatment (Intermountain INSPIRE Registry) purpose is to collect biological samples, clinical information and laboratory data from Intermountain Healthcare patients. The registry originally collected samples in patients undergoing a coronary angiography as part of the Intermountain Heart Collaborative Study. It has been expanded to collect samples in patients diagnosed with all types of medical conditions, and patients from the general population including those who have not been diagnosed with health related issues. Just over 25,000 individuals have provided samples as part of this registry. The registry enables researchers to develop a comprehensive collection of information that may help in disease management, including determining best medical practices for predicting, preventing and treating medical conditions.

  Study phs001545

• Transcriptomic analysis of B-cell acute lymphoblastic leukaemia (B-ALL) patients treated on the ALL09 clinical trial

  This study provides comprehensive transcriptomic analysis of adolescent and young adult (AYA) patients treated on the Australasian Leukaemia and Lymphoma Group (ALLG) ALL09 clinical trial (ACTRN12618001734257). The ALL09 clinical trial is a Phase II single arm study to assess whether substitution of blinatumomab for conventional multi-agent chemotherapy in phase 2 induction leads to improved minimal residual disease negativity rates when compared to the historical AYA ALL trial cohort. Patients treated on this trial were aged 15-40 years, demonstrated morphological diagnosis of CD19 positive B-lineage acute lymphoblastic leukaemia (B-ALL), and were negative for Philadelphia chromosome-positive disease. Transcriptomic sequencing was performed as a correlative study to determine assess patients’ genomic subtypes and enable comparison of clinical outcome in blinatumomab treated patients.

  Study EGAS50000001109

• Ribosome profiling shows variable sensitivity to detect open reading frames for conventional and different types of cryptic T cell antigens

  The aim of the study was to explore the sensitivity of ribosomal profiling to detect ORFs for cryptic antigens targeted by T cells in immune responses. Ribosomal profiling was performed for six EBV-LCLs. Detection of conventional and cryptic MiHA-encoding ORFs was compared. The data showed that open reading frames (ORFs) for conventional MiHAs as well as cryptic MiHAs in upstream ORFs were frequently detected with similar sensitivity. However, only a limited number of MiHAs in in reading frames alternative to protein-coding sequences and no ORFs derived from long non-coding RNAs were detected. In conclusion, Ribo-seq for identification of antigen-encoding ORFs is useful to screen for cryptic antigens in upstream ORFs as potential targets for immunotherapy.

  Study EGAS50000000322

• RNA sequencing data from glioblastoma primary cell lines treated with indisulam

  This study aimed to develop NovumRNA, a bioinformatics pipeline designed to predict non-canonical tumor-specific antigens (ncTSAs) from human tumor RNA-sequencing data, potentially broadening the target pool for cancer neo-epitope-based immunotherapies. The splicing-modulating drug indisulam was investigated for its potential to induce aberrant transcriptomes, potentially increasing ncTSAs, subsequently predicted by NovumRNA. Four glioblastoma primary cell lines were derived from patient Cavitron Ultrasonic Aspirator (CUSA) material, cultured as neurospheres, and treated with indisulam or vehicle control. RNA was extracted at 6 and 16 hours post-treatment and sequenced using the NovaSeq platform. The resulting RNA-seq data was analyzed with NovumRNA, using healthy brain GTEx samples as controls, to identify and validate ncTSAs induced by indisulam treatment. NovumRNA is available at: https://github.com/ComputationalBiomedicineGroup/NovumRNA.

  Study EGAS50000000680

• Clinical relevance of TCGA subtypes for gastric cancer patients

  There is a clinical need for the availability of molecular biomarkers in the tratment of gastric cancer (GC), since survival rates remain poor with a 5-year survival rate of only ~`40% for patients with resectable disease. These markers will elad to a more tailored approach in the treatment of GC, which enhances efficacy and reduces toxicity. Recently, The Cancer Genome Atlas (TCGA) classified GC patients into four molecular subgroups: Epstein Barr Virus positive (EBV+), genomically stable (GS), microsatellite instable (MSI), and chromosomal instable (CIN). For this purpose we aim to collect tumor tissue blocks from patients who participated in the Dutch D1/D2 or the CRITICS trial and who gave informed consent for translational studies. Associations between TCGA subtypes and outcomes to these different therapeutic options will be analyzed.

  Study EGAS50000000779

• RNA-Seq of human longitudinal whole blood samples from PCR-positive and PCR-negative recent household contacts of COVID-19 index cases.

  Little is known about the transcriptomic profile of individuals who are exposed to SARS-CoV-2 yet resist becoming PCR positive. To investigate this, longitudinal whole-blood samples were taken (0, 7, 14, and 28 days after enrolment) from PCR positive and PCR negative SARS-CoV-2-naïve household contacts who were recently exposed to a COVID-19 index. Samples were also taken from pre- and post-pandemic unexposed controls. Total RNA was extracted from PAXgene tubes before undergoing poly(A) selection followed by globin and rRNA depletion. DNA libraries were constructed using the NEBNext® Ultra™ II Directional RNA Library Prep Kit for Illumina. All samples were then sequenced across 2 flowcells of an Illumina HiSeq 4000.

  Study EGAS50000000473

• UCSF Pediatric Bithalamic Glioma Genome Project

  Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. We performed targeted next-generation sequencing of approximately 500 cancer-associated genes on a cohort of 13 pediatric bithalamic diffuse gliomas, a lethal brain tumor of childhood for which the genetic basis is largely unknown. We identified that bithalamic diffuse gliomas harbor frequent mutations in the EGFR oncogene in the absence of accompanying gene amplification and only rare histone H3 mutation. These EGFR mutations were either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain). Accompanying alterations included frequent TP53 mutation, CDK6 amplification or CDKN2C mutation, and BCOR and BCORL1 mutation or deletion.

  Study EGAS00001004033

• Genetic landscape of malignant peripheral nerve sheath tumors

  Neurofibromatosis 1 is a hereditary syndrome characterized by the development of numerous benign neurofibromas, a small subset of which progress to malignant peripheral nerve sheath tumors (MPNSTs). To better understand the genetic basis for MPNSTs, we performed whole genome sequencing on four MPNSTs from patients with neurofibromatosis 1 and found that each of them had a somatic, inactivating mutation of SUZ12, a chromatin modifying gene adjacent to the NF1 gene responsible for the benign neurofibromas in these patients. We then performed targeted sequencing on an additional 46 MPNSTs and found that 12 had somatic mutations in SUZ12. Fifteen of the 17 (88%) mutations in SUZ12 were predicted to inactivate protein function, implicating it as a tumor suppressor gene possibly responsible for the progression from neurofibromas to MPNTs.

  Study EGAS00001000974

• Exome sequence data for germline, primary tumor, and relapse tumor of a transformed non-Hodgkins lymphoma patient with unexpected long-time remission

  The patient was diagnosed with a transformed high-grade non-Hodgkin lymphoma stage III, and treated with conventional R-CHOP (Rituximab (R), Cyclophosphamide (C), Doxorubicin (H), Vincristine (O) and Prednisone (P)). Unfortunately, she suffered from severe toxicity but recovered during the following six months remission until a biopsy verified relapse. The patient refused second line combination chemotherapy, but accepted a 3 months palliation with R and Chlorambucil. Unexpectedly, she obtained continuous complete remission and is at present >9 years after primary diagnosis.Molecular studies and data evaluation by principal component analysis, mutation screening, and copy number variations of the primary and relapsed tumor, identified patterns of branched lymphoma evolution, most likely diverging from an unknown in situ follicular lymphoma.

  Study EGAS00001001973

• High-resolution structural genomics reveals new therapeutic vulnerabilities in glioblastoma

  We investigated the role of 3D genome architecture in instructing functional properties of glioblastoma stem cells (GSCs) by generating the highest-resolution 3D genome maps to-date for this cancer. Integration of DNA contact maps with chromatin and transcriptional profiles identified specific mechanisms of gene regulation, including individual physical interactions between regulatory regions and their target genes. Residing in structurally conserved regions in GSCs was CD276, a gene known to play a role in immuno-modulation. We show that, unexpectedly, CD276 is part of a stemness network in GSCs and can be targeted with an antibody-drug conjugate to curb self-renewal, a key stemness property. Our results demonstrate that integrated structural genomics datasets can be employed to rationally identify therapeutic vulnerabilities in self-renewing cells.

  Study EGAS00001003493

• Whole exome sequencing in RVOT patients

  In a patient with right ventricular outflow tract (RVOT) tachycardia we identified a heterozygous point mutation in the selectivity filter of the stretch-activated K2P potassium channel TREK-1 (KCNK2 or K2P2.1). This mutation introduces abnormal sodium permeability to TREK-1 In addition, mutant channels exhibit a hypersensitivity to stretch-activation, suggesting that the selectivity filter is directly involved in stretch-induced activation and desensitization. Increased sodium permeability and stretch-sensitivity of mutant TREK-1 channels may trigger arrhythmias in areas of the heart with high physical strain such as the RVOT. We present a pharmacological strategy to rescue the selectivity defect of the TREK-1 pore. Our findings provide important insights for future studies of K2P channel stretch-activation and the role of TREK-1 in mechano-electrical feedback in the heart.

  Study EGAS00001002319

• The Precision Medicine in Liver Cancer across an Asia-pacific NETwork (PLANET)

  Hepatocellular carcinoma (HCC) is the 2nd most important cause of cancer deaths in the world. The outcomes of treatment in HCC are poor compared to other common cancers because there are no good systemic therapy drugs. We designed a prospective study that will involve 5 different sites within the established Asia-Pacific Hepatocellular Carcinoma Trials Group to study both the genetics as well as immune profiles of HCC in different ethnicities. In this study, patients will be followed-up and at recurrence the tissues to understand the evolution of disease progression. Here, we presented both the genomic (DNA) and phenotypic (RNA) evolution for the first batch of 56 patients. The detailed findings will be listed in the corresponding publication soon.

  Study EGAS00001003813

• A genetic compendium of human brains from the UK Medical Research Council brain tissue resource

  Common neurodegenerative diseases have a complex genetic architecture. Highly penetrant diseases alleles are found in a significant minority of cases, and common risk alleles are present in a large proportion. Given the central role of genetic factors in the pathogenesis of these disorders, it is critical that mechanistic studies in human subjects and tissue samples are interpreted in an genetically enlightened context. To address this we performed exome sequencing on 1461 human brains accessible through the Medical Research Council (UK) brain banks network. Our findings confirm the complex genetic landscape of neurodegenerative disease. Clinical, pathological and genetic data for the 1461 brains with corresponding exome sequencing data are available within this dataset, enabling the genetic stratification and selection of post-mortem tissue samples for researchers.

  Study EGAS00001001599

• Spatio-temporal evolution of the primary glioblastoma genome

  Tumor recurrence following treatment is the major cause of mortality for glioblastoma multiforme (GBM) patients. Thus, insights on the evolutionary process at recurrence are critical for improved patient care. Here, we describe our genomic analyses of 38 GBM patients with the initial and recurrent tumor specimens for each individual. A substantial divergence in the landscape of driver alterations was associated with distant appearance of a recurrent tumor from the initial tumor, suggesting that the genomic profile of the initial tumor can mislead targeted therapies for the distally recurred tumor. In addition, in contrast to IDH1-mutated gliomas, IDH1-wild-type primary GBMs rarely developed hypermutation following temozolomide (TMZ) treatment, indicating low risk of TMZ-induced hypermutation for these patients under the standard regimen.

  Study EGAS00001001041

• Whole Genome Sequencing of Liver Cancers

  Genomic alterations driving tumorigenesis result from the interaction of environmental exposures and endogeneous cellular processes. With a diversity of risk factors including viral infection, carcinogenic exposures and metabolic diseases, liver cancer is an ideal model to study these interactions. Whole genome sequencing of liver tumors identified 10 mutational signatures showing distinct relationships with environmental exposures, replication and transcription. Transcription-coupled damage was specifically associated with the liver-specific signature 16 and alcohol intake. Flood of indels were identified in very highly expressed hepato-specific genes, likely resulting from replication-transcription collisions. Reconstruction of sub-clonal architecture revealed mutational signature evolution during tumor development exemplified by the vanishing of aflatoxin-B1 signature in African migrants. These findings shed new light on the natural history of liver cancers

  Study EGAS00001002408

• Non-Mendalian inheritance of extrachromosal DNA elements can drive disease evolution in glioblastoma

  Genomic heterogeneity of glioblastoma (GBM) is suspected to contribute to the poor response to therapy of this disease. We compared molecular characteristics between primary GBM, neurospheres and orthotopic xenograft models derived from the same parental tumor. Driver alterations were in majority propagated from tumor to model systems. Extrachromosomal amplifications of MET, a proto-oncogene coding for a receptor tyrosine kinase, were detected in three primary GBM, largely discarded in neurospheres cultures, but resurfaced in xenografts. The clonal dynamics inferred by somatic single nucleotide variants (sSNVs) in MET-amplified samples diverged from the pattern delineated by the MET amplification event suggesting that the MET event and sSNVs were inherited in different manners. Our analysis shows that extrachromosomal elements are able to drive tumor progression.

  Study EGAS00001001878

• MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition

  Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low “variant” subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which combined with chemotherapy strongly suppresses tumor progression and increases survival. These data identify molecular features for patient stratification and uncover a novel targeted treatment approach for MYC-driven SCLC.

  Study EGAS00001002115

• An Unusual Genomic Variant of Pancreatic Ductal Adenocarcinoma with an Indolent Clinical Course

  We describe a patient with biopsy-proven locally advanced pancreatic ductal adenocarcinoma (PDA) who underwent a modified course of gemcitabine and stereotactic body radiation therapy. Whole exome sequencing of this patient's tumor revealed a simple genome landscape with no evidence of mutations, copy number changes, or structural alterations in genes most commonly associated with PDA, i.e. KRAS, CDKN2A, TP53 or SMAD4. An analysis of germline DNA revealed no pathogenic variants of significance. Whole exome and whole genome sequencing identified a somatic mutation of RNF213 and an inversion/deletion of CTNNA2 as the genetic basis of this PDA. Although PDA is classically characterized by a predictable set of mutations, these data suggest that alternate genetic paths to PDA may exist, which can be associated with a more indolent clinical course.

  Study EGAS00001002192

• Most HCCs in Taiwan show the mutational signature of aristolochic acid

  Plants in the genus Aristolochia contain the mutagen aristolochic acid (AA) and have been widely used in traditional medicines and for weight loss. AA binds covalently to genomic DNA and induces a highly distinctive mutational signature. While AA involvement in urinary-tract cancers in Taiwan is known, the possible role of AA in hepatocellular carcinomas (HCCs) in Taiwan has not been examined. Here, we whole-exome sequenced 98 unselected HCCs from Taiwan and analyzed the mutational signatures for evidence of AA mutagenesis. Remarkably, more than 78% of HCCs showed strong evidence of AA mutagenesis, often associated with high mutation burdens. Non-synonymous mutations in genes known to be HCC driver genes were detected. Importantly, we elucidated the potential of immunotherapy in this cohort of liver cancer patients.

  Study EGAS00001002301

• Circulating cell-free DNA analysis in Small Cell Lung Cancer

  Small cell lung cancer (SCLC) accounts for ~250,000 deaths worldwide each year. Acquisition of adequate tumour biopsies is challenging and liquid biopsies present the best option for patient stratification and response monitoring. We present genome-wide and targeted plasma DNA sequencing data that identifies tumour related changes in 91% of limited (LS-SCLC) and 100% of extensive stage (ES-SCLC) patients. Parallel analysis of circulating tumour cells (CTCs, by CellSearch) based on ≥ 1 CTC/7.5ml blood increased tumour detection frequencies to 98% patients (95% for LS-SCLC) where CTC count and plasma DNA readouts correlated with disease stage and overall survival (OS). Targeted plasma DNA sequencing identified potential therapeutic targets in >50% of patients. This approach will support trials of targeted therapies where improved patients outcomes are urgently required.

  Study EGAS00001003110

• RNA-seq of Glioblastoma stem cells

  Chromatin accessibility discriminates stem from mature cell populations, enabling the identification of primitive stem-like cells in primary tumors, such as Glioblastoma (GBM) where self-renewing cells driving cancer progression and recurrence are prime targets for therapeutic intervention. We show, using single-cell chromatin accessibility, that primary GBMs harbor a heterogeneous self-renewing population whose diversity is captured in patient-derived glioblastoma stem cells (GSCs). In depth characterization of chromatin accessibility in GSCs identifies three GSC states: Reactive, Constructive, and Invasive, each governed by uniquely essential transcription factors and present within GBMs in varying proportions. Orthotopic xenografts reveal that GSC states associate with survival, and identify an invasive GSC signature predictive of low patient survival. Our chromatin-driven characterization of GSC states improves prognostic precision and identifies dependencies to guide combination therapies.

  Study EGAS00001003070

• Exome_sequencing_of_thyroid_disease_in_Val_Borbera

  The Val Borbera is a region characterized by low iodine and high prevalence of thyroid disorders, the commonest endocrine disorders in the general population. About 30% of the participants of the Val Borbera Project were affected by such disorders and were characterized by several parameters, TSH level, anti TPO antibodies, echography, family origin. Individuals with extreme phenotypes were identified and could be clustered based on family origin and genotype. We propose to exome sequence 6 of them, affected with true goiter, at high dept (40-60x) to obtain information on exonic rare variants. Due to the family structure and to the availability of whole genome sequence information on 110 individuals from the isolated population we expect to be able to identify putative causative variants for thyroid disorders that may be studied in the remaining affected individuals.

  Study EGAS00001000344

• Tumor-associated preferred end coordinates and somatic variants as signatures of circulating tumor DNA

  Cell-free DNA fragmentation is a nonrandom process. We showed that cell-free DNA fragments with ends at certain genomic coordinates had higher likelihoods of being derived from hepatocellular carcinoma. Other coordinates were associated with cell-free DNA molecules originating from the liver. Quantitative assessment of cell-free DNA molecules bearing these respective groups of end signatures correlated with the amounts of tumor-derived or liver-derived DNA in plasma. There were millions of tumor-associated plasma DNA end coordinates across the genome. Due to their high prevalence, they were more readily detectable than somatic mutations as a cancer signature in plasma. Hence, detection of tumor-associated plasma DNA ends may offer a cost-effective means of capturing evidence for the presence of cancer through liquid biopsy assessment.

  Study EGAS00001003160

• Mutations in the SIX1/2 pathway and the DROSHA/DGCR8 miRNA microprocessor complex underlie high-risk blastemal type Wilms tumors

  Blastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. In order to find novel therapeutic leads for this subgroup of patients, we analyzed 58 such Wilms tumors by exome and transcriptome analysis and validated our findings in larger independent cohorts. Recurrent mutations identified either somatically or in the germline included a hotspot mutation (Q177R) in the homeodomain of SIX1 and SIX2 in tumors with high proliferative potential, mutations in microprocessor genes like DROSHA, DGCR8, DICER1 and DIS3L2, and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations had a strong effect on miRNA profiles in tumors, which we confirmed in cell lines transfected with mutant DROSHA.

  Study EGAS00001000906

• The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer

  Reactivation of telomerase reverse transcriptase (TERT) expression enables cells to overcome replicative senescence and escape apoptosis, fundamental steps in the initiation of human cancer. Multiple cancer types, including up to 83% of glioblastomas (GBM), harbor highly recurrent TERT promoter mutations of unknown function but specific to two nucleotide positions. We identify the functional consequence of these mutations in GBM to be recruitment of the multimeric GABP transcription factor specifically to the mutant promoter. Allelic recruitment of GABP is consistently observed across four cancer types, highlighting a shared mechanism underlying TERT reactivation. Tandem flanking native ETS motifs critically cooperate with these mutations to activate TERT, likely by facilitating GABP heterotetramer binding. GABP thus directly links TERT promoter mutations to aberrant expression in multiple cancers.

  Study EGAS00001001242

• Molecular sub-classification of hormone receptor-positive breast cancer

  Patients with estrogen and/or progesterone receptor-positive breast cancer benefit from hormonal treatment, yet high global death burdens due to high prevalence and long-term recurrence risk call for biomarkers to guide additional treatment approaches. From a prospective, observational study of postmenopausal early breast cancer patients treated with tamoxifen or aromatase inhibitors gene expression analyses of 612 tumors was performed using the NanoString® Breast Cancer 360 panel. We identified novel gene expression signatures, i.e. BRCAness and Tumor Inflammation Signature (associated with high tumor lymphocyte infiltration), that may aid to select high-risk patients in order to improve adjuvant treatment by targeting DNA repair deficiency or immune-checkpoints in addition to standard chemo-endocrine treatment. The overall goal is to foster novel concepts for a stratified early breast cancer management.

  Study EGAS00001004594

• Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome

  Patients with short QT syndrome (SQTS) may present with syncope, ventricular fibrillation or sudden cardiac death. Six SQTS susceptibility genes, encoding cation channels, explain less than 25% of SQTS cases. Here we identify a missense mutation in the anion exchanger (AE3)-encoding SLC4A3 gene in two unrelated families with SQTS. The mutation causes reduced surface expression of AE3 and reduced membrane bicarbonate transport. Slc4a3 knockdown in zebrafish causes increased cardiac pHi, short QTc, and reduced systolic duration, which is rescued by wildtype but not mutated SLC4A3. Mechanistic analyses suggest that an increase in pHi and decrease in [Cl-]i shortened the action potential duration. However, other mechanisms may also play a role. Altered anion transport represents a mechanism for development of arrhythmia and may provide new therapeutic possibilities.

  Study EGAS00001002632

• Patient-derived organoids as a novel tool to study cervical cancer

  Cervical cancer is the most prevalent gynecological malignancy worldwide, often caused by infection with a high-risk human papillomavirus. Currently, there are only limited number of human-derived culture systems available that enable to study the viral infection for short-term. Here, we report on establishment of long-term human-derived organoid cultures from both healthy ecto- and endocervical epithelia that closely recapitulate the tissues of origin by maintaining the authentic histological and tissue-specific gene expression profiles. Additionally, using material from patients’ Pap-brush material, a successful panel of long-term patient-derived cancer organoids was established that maintain the causative viral infection in vitro and show differential response to common chemotherapy regimens. This study provides a promising platform for cervical cancer research and studying direct virus-host interactions.

  Study EGAS00001004439

• Phase Ib of olaparib and capivasertib

  Background: Combining poly(ADP-ribose) polymerase (PARP) with phosphatidylinositol-3-kinase (PI3K) pathway inhibitors is supported by strong preclinical rationale. We sought to assess safety and a recommended phase 2 dose (RP2D) for the PARPi olaparib combined with the AKT inhibitor, capivasertib, and evaluate molecular markers of response and resistance. Methods: As part of a larger phase 1b trial, we performed a safety lead in of olaparib and capivasertib followed by expansion (n=24) in endometrial, triple negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300mg orally twice daily and capivasertib orally twice daily on a 4 day on/3 day off schedule were evaluated. Two dose levels (DL) were planned: capivasertib 400mg (DL1); capivasertib 320mg (DL-1). Patients underwent biopsies at baseline and after 28 days.

  Study EGAS00001004930

• Assessment of the Toll-like receptor 3 response in hepatocytes

  Toll like receptor 3 (TLR3) is an endosomal pattern recognition receptor (PRR), recognizing double stranded RNA (dsRNA) as a distinct Pathogen-associated molecular pattern (PAMP) for viral infections. We aim to understand the contribution of TLR3 to the dsRNA response in hepatocytes. The innate immune response of cells of hepatic origin (Huh7, Huh7.5, PH5CH and primary human hepatocytes (PHH)) was analyzed by transcriptome analysis (RNAseq) upon supernatant delivery or transfection of synthetic dsRNA (poly(I:C)). Expression of TLR3 and RIG-I was reconstituted by lentiviral transduction in Huh7 and Huh7.5 cells. Huh7 and Huh7.5 cells, devoid of functional TLR3 expression, did not respond to supernatant delivery of poly(I:C), in contrast to PH5CH and PHH, confirming a high selectivity of this method towards activating TLR3 in all hepatocyte models.

  Study EGAS00001005147

• Multiple migrations to the Philippines during the last 50,000 years

  A key link to understand human history in Island Southeast Asia is the Philippine archipelago and its poorly investigated genetic diversity. We collected and analyzed the most comprehensive set of population-genomic data for the Philippines, 1028 individuals covering 115 indigenous communities. We demonstrate that the Philippines were populated by at least five waves of human migration. The Cordillerans migrated into the Philippines prior to the arrival of rice agriculture, where some remain to be the least admixed East Asians carrying an ancestry shared by all Austronesian-speaking populations; thereby challenging an exclusive Out-of-Taiwan model of joint farming-language-people dispersal. Altogether, our findings portray Philippines as a crucial gateway, with a multilayered history, that ultimately changed the genetic landscape of the Asia-Pacific region.

  Study EGAS00001005083

• Personalised therapy with MEK inhibition leads to a sustained complete response in an adolescent patient with a recurrent malignant peripheral nerve sheath tumor

  The prognosis of recurrent malignant peripheral nerve sheath tumors (MPNST) is dismal, with surgical resection being the only definitive salvage therapy. Treatment with chemo-radiation approaches has not significantly improved patient outcomes. Similarly, trials of therapies targeting MPNST genomic drivers have thus far been unsuccessful. Improved understanding of the molecular pathogenesis of MPNST indicates frequent activation of the mitogen activated protein kinase (MAPK) cell signaling pathway. MEK inhibitors have shown activity in preclinical studies; however, their clinical efficacy has not been reported to date. We describe here a case of sustained complete response to MEK inhibition in an adolescent patient with a recurrent metastatic MPNST with multiple alterations in the MAPK pathway, guided by a precision oncology approach.

  Study EGAS00001004899

• RP-1843 Arcagen - Gastrointestinal rare cancers (GI)

  Arcagen is an EORTC/SPECTA pan-European project that aims to recruit 1000 rare cancer patients from different tumour domains of EURACAN. This study collected samples from advanced or metastatic rare cancer from patients older than 12, and analysed them using Foundation Medicine next-generation sequencing (NGS) panels (FoundationOne CDx for FFPE samples or FoundationOne Liquid CDx for blood samples). Here we are submitting two datasets that contain NGS files from gastrointestinal rare cancers (n=119): - Dataset 1 (32 patients): Mesothelioma of the peritoneum (n=21) and Pseudomyxoma peritonei/mucinous adenocarcinoma of the appendix (n=11) - Dataset 2 (87 patients): Intra-hepatic cholangiocarcinoma (n=47), Extra-hepatic, cholangiocarcinoma (n=16), Not specified Cholangiocarcinoma (n=9), Small bowel adenocarcinoma (n=6) and other rare GI cancer (n=9)

  Study EGAS00001006299

• Upper respiratory microbiome of COVID-19 patients

  Understanding the pathology of COVID-19 is a global research priority. Early evidence suggests that the microbiome may be playing a role in disease progression, yet current studies report contradictory results. Here, we examine potential confounders in COVID-19 microbiome studies by analyzing the upper respiratory tract microbiome in well-phenotyped COVID-19 patients and controls combining microbiome sequencing, viral load determination, and immunoprofiling. We found that time in the intensive care unit and the type of oxygen support explained the most variation within the upper respiratory tract microbiome, dwarfing (non-significant) effects from viral load, disease severity, and immune status. Specifically, mechanical ventilation was linked to altered community structure, lower species- and higher strain-level diversity, and significant shifts in oral taxa previously associated with COVID-19.

  Study EGAS00001004951

• Lung Adenocarcinoma Promotion by Air Pollutants

  A complete understanding of how environmental carcinogenic exposures promote cancer formation is lacking. Over 70 years ago, tumour formation was proposed to occur in a two step process: an initiating step which induces mutations in normal tissue, followed by a promoter step which triggers cancer development. Recent evidence has revealed healthy human tissue contains a patchwork of clones harbouring oncogenic mutations.This led us to hypothesise that environmental particulate matter measuring PM2.5, known to be associated with lung cancer risk, might promote lung cancer by acting on pre-existing cells harbouring oncogenic mutations in normal lung tissue. Here we use a combination of WGS and RNA-seq of mouse tumours from pollution-exposed mice to examine the impact of particulate matter on mutagenesis and gene expression respectively.

  Study EGAS00001006951

• The long term effects of chemotherapy on normal blood - Nanoseq dataset

  In developed countries, ~10% of individuals are exposed to systemic chemotherapy for cancer and other diseases. Many chemotherapeutic agents act by increasing DNA damage in cancer cells, hence triggering cell death. However, there is limited understanding of the extent and consequences of collateral DNA damage to normal tissues. To investigate the impact of chemotherapy on mutation burdens and cell population structure of a normal tissue we sequenced blood cell genomes from 23 individuals, aged 3-80 years, treated with a range of chemotherapy regimens. Substantial additional mutation loads with characteristic mutational signatures were imposed by some chemotherapeutic agents, but there were differences in burden between different classes of agent, different agents of the same class and different blood cell types. Chemotherapy also induced premature changes in the cell population structure of normal blood, similar to those of normal ageing. The results constitute an initial survey of the long-term biological consequences of cytotoxic agents to which a substantial fraction of the population is exposed during the course of their disease management, raising mechanistic questions and highlighting opportunities for mitigation of adverse effects.

  Dataset EGAD00001015340

• Genome-wide associations of human gut microbiota variation and implications for causal inference analyses

  Here we use appropriate taxon-specific models along with support from independent cohorts to show association between human host genotype and gut microbiome variation. Using fecal derived 16S rRNA gene sequences and host genotype data from the Flemish Gut Flora Project (FGFP) we identify genetic associations involving multiple microbial traits. Mendelian randomization analysis was able to estimate associations between microbial traits and disease, however in the absence of clear microbiome driven effects, caution is needed in interpretation. This work marks a growing catalog of genetic associations which will provide insight into the contribution of host genotype to gut microbiome. Despite this, the uncertain origin of association signals will likely complicate future work looking to dissect function or use associations for causal inference analysis.

  Study EGAS00001004420

• University of Alabama at Birmingham (Xenotransplantation Project) - DAC

  This is a Data Access Committee (DAC) developed to govern access to sequence level data produced by the Porrett Lab, University of Alabama at Birmingham (Xenotransplantation Project), and headed by Dr. Jayme Locke, and Dr. Porrett M. Paige, Principal, and Co-Principal Investigators respectively. These data were largely used in the generation of the manuscript: “Spatiotemporal immune atlas of the first clinical-grade gene-edited pig-to-human kidney xenotransplant”. Access to these data will be granted to qualified investigators for appropriate use following data use approval from members of the DAC.

  Dac EGAC50000000188

• Mid-frequency hearing loss is a characteristic clinical feature of OTOA-associated hearing loss

  In this study, we performed NGS analysis of a large Japanese hearing loss cohort, and identified 7 patients with OTOA-associated hearing loss. As novel clinical features identified in this study, the audiometric configurations of OTOA-associated hearing loss patients was found to be mid-frequency.

  Study JGAS000200

• Data Access Committee for the DNA sequencing data included in the study "Multifocal cohort analysis unveils cell types associated with regional lymph node seeding in prostate cancer".

  A data transfer agreement (DTA), based on the example DTA provided by UZ Gent, is to be filled out by the requester and Multifocal RNA-seq and tNGS data from primary and metastatic tissues of locally advanced and de novo metastatic cohorts - Data Access Committee. https://www.uzgent.be/nl/over-uz-gent/organisatie/data-access-comite/wat-zijn-de-opdrachten-van-het-data-access-comite Coordinator: Muriel Fouquet E-mail: dataaccesscommittee@uzgent.be

  Dac EGAC50000000930

• scRNA-seq of a 3D human cortical tissue model from human iPSCs exploring 2D versus 3D co-culturing

  Single-cell RNA-seq analysis of human iPSC-derived microglia/astrocytes/neurons in a novel, human in vitro 3D cortical tissue model, as well as 2D co-cultures for comparison. Samples include distinct conditions as described in the Study section. The dataset was generated using the BD Rhapsody technology and sequenced paired-end with Illumina NovaSeq2000. Information on the multiplexing of samples is reported in the Analyses section.

  Dataset EGAD50000002021

• cfDNA sWGS BAM — Healthy donors

  Paired-end shallow whole-genome sequencing (sWGS) of plasma cfDNA from healthy donors recruited at EFS Montpellier (France). Libraries: DSP (NEBNext Ultra II) and/or SSP (IDT/Swift Accel-NGS 1S Plus). Sequencing by IntegraGen (France, 2022–2024). Reads aligned to GRCh38 (hg38 canonical) with BWA-MEM; BAMs coordinate-sorted and indexed; submission contains primary mapped reads only (unmapped/secondary/supplementary/duplicates removed; typical filter “-F 3332”, MAPQ threshold as noted in analysis records). Each BAM/BAI pair is linked to its Sample and Experiment. Data Use: controlled access.

  Dataset EGAD50000001880

• Whole-genome and single-cell sequencing of lethal metastatic castration resistant prostate cancer

  Contains a total of 9 patients with whole-genome sequencing of 30 tumours or germline samples, 10X single-cell multiome RNA-seq + ATAC-seq of 24 tumours, 10X 5' single-cell RNA-seq of 10 tumours, and snPATHO-seq of 2 primary tumours. All single-cell experiments have matched whole-genome sequencing. When matched tumour (and germline) whole-genome sequencing is missing, it can be found under EGAS00001006598.

  Dataset EGAD50000001869

• TenK10K Phase 1: Whole Genome Sequencing SNP + indels multi-sample VCFs

  SNP and indel variants were called for 1,925 samples from phase 1 of the TenK10K project. Variant calling from WGS alignments to the GRCh38 reference assembly was performed using GATK4 HaplotypeCaller in DRAGEN mode. These VCFs consist of common (>=1% minor allele frequency [MAF]) and rare (<1% MAF) variants . This dataset is comprised of autosomal variants provided as multisample compressed VCF format files. Principal component scores were derived by using gnomAD’s run_pca_with_relateds method.

  Dataset EGAD50000002377

• De novo modeling of chromoplectic Ewing sarcoma tumors from patient-derived mesenchymal stem cells

  Ewing sarcoma is characterized by pathognomonic translocations fusing most frequently EWSR1 with FLI1 (EF1). In addition, Ewing sarcoma can also display alterations in STAG2, TP53 and CDKN2A (SPC). Starting from Ewing sarcoma derived human mesenchymal stem cells (MSCpat), we recapitulated this translocation and SPC alterations using a CRISPR/cas9 approach and generated a bona fide Ewing sarcoma model (EWIma1) displaying transcriptomic (RNA-seq) and epigenetic (ChIP-seq) hallmarks of EwS.

  Dataset EGAD50000001673

• Tumor Profiler Project - OV scDNA data additional samples

  The dataset contains 10x Chromium single-cell DNA sequencing data from 6 samples from 5 different patients with ovarian cancer. 4 samples were collected from the tumor, and 2 samples from ascites. Sequencing was performed in paired-end mode and sequencing data is provided in fastq format. This dataset contains additional samples from patients not classified as having high-grade serous adenocarcinoma.

  Dataset EGAD50000001294

• Tumor Profiler Project - OV scRNA data additional samples

  The dataset contains 10x Chromium single-cell transcriptomics data from 6 samples from 4 different patients with ovarian cancer. 3 samples were collected from the tumor, 3 samples from ascites. Sequencing was performed in paired-end mode and sequencing data is provided in fastq format. This dataset contains additional samples from patients not classified as having high-grade serous adenocarcinoma.

  Dataset EGAD50000001293

• RnaSeq data from 414 tumor samples with non muscle invasive bladder cancer

  A better understanding of the molecular landscape of non-muscle-invasive bladder cancer (NMIBC) is essential to improve risk assessment and identify potential therapeutic targets. Here, we perform a comprehensive genomic analysis of patients diagnosed with NMIBC based on whole-exome- (n=438), shallow whole-genome- (n=362), and total RNA-sequencing (n=414). This dataset contains 414 BAM files corresponding to the full total RNA-sequencing dataset.

  Dataset EGAD50000000733

• WES data from study: Molecular underpinnings of dedifferentiation and aggressiveness in chromophobe renal cell carcinoma

  The ChRCC study WES dataset contains raw whole exome sequencing data of 17 tumor and 7 adjacent normal samples from 7 UTSW patients, who have consented to depositing their genomic data to public repository. WES was performed using 75bp paired-end fragments at an average read depth > 100x on a HiSeq2500 platform (Illumina, San Diego, CA, USA). The raw data is in fastq format.

  Dataset EGAD50000000415

• Evaluating potential drug candidates for the treament of Henamgiopericytoma on patient derived cell line models

  Solitary fibrous tumor/Hemangiopericytoma (SFT/HPC) is a rare subtype of soft tissue sarcoma associated with NAB2-STAT6 gene fusions. This study established and characterized a novel SFT/HPC patient-derived cell line called SFT-S1. Potential drug candidates that could be repurposed for the treatment of SFT/HPC were screened. Screening was performed through RNA-Seq

  Dataset EGAD50000000039

• The impact of the human leukaemia virus HTLV-1 on host gene expression

  PBMCs were purified from blood samples of 8 HTLV-1 infected individuals, and cryo-preserved in fetal calf serum containing 10% DMSO. DNA from each samples was extracted using Qiagen Blood &amp; Tissue kit according to the manufacturer's protocol. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute please see http://www.sanger.ac.uk/datasharing/ .

  Dataset EGAD00001004169

• Non-ADT METs ICGC Prostate UK

  To characterize the subclonal genomic architecture of non-androgen-deprived metastatic prostate cancer, we performed whole-genome sequencing (WGS) of pelvic lymph node metastases and matching noncancerous blood from 10 patients to an average sequencing depth of 55x. The patients are part of PELICAN (Project to ELIminate Lethal Cancer) study led by G. Steven Bova at Johns Hopkins University (USA) and Tampere University (Finland). As of September 2020, study using these data is: Wedge et al, Nature Genetics 2018 (PMID: 29662167)

  Dataset EGAD00001002002

• Analysis of tumor periphery and center-specific mutations in renal cell carcinoma

  Renal cell carcinoma (RCC) is a genomically heterogeneous tumor. In the present project, the question whether intratumoral heterogeneity follows a zonal pattern indicating spatial niches was addressed. Whole exome sequencing of 16 paired samples from tumor periphery and center revealed a number of region-specific functional SNVs and Indels. Therefore, RCCs are not composed of evenly admixed tumor cells but show topological differences in their clonal composition.

  Dataset EGAD00001002067

• Whole exome sequencing of young onset Primary Sclerosing Cholangitis

  Primary sclerosing chloangitis is a rare autoimmune disease of the liver (prevalence =10/100,000) with a mean age of onset of 40 years. We are currently undertaking GWASand immunochip experiments to identify loci underlying PSC susceptibility. Through ourcollaborators at the University of Calgary we have access to DNA from three parent-offspringtrios where the children required liver transplants due to PSC before the age of 9. These areextremely rare cases indeed and we believe that exome-sequencing represents a powerfulmeans of identifying the causal mutation underlying this severe phenotype.

  Dataset EGAD00001000671

• Sequencing probands and families with severe insulin resistance syndromes

  This is an ongoing project and continuation to all the sequencing we have been doing over the last few years. We have some additional families and probands with syndromes of insulin resistance not previously sequenced within uk10k or other core funded projects. We would like to complete the sequencing in all of the good quality families and probands we have, this would require another ~50 samples to be WES sequenced. This cohort has already proven to be a rich source of interesting findings with papers in Science and Nature genetics.

  Dataset EGAD00001000694

• Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4

  Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is an extremely rare, aggressive cancer affecting children and young women. We identified germline and somatic inactivating mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 75% (9/12) of SCCOHT patients in addition to SMARCA4 protein loss in 82% (14/17) of SCCOHT tumors, but in only 0.4% (2/485) of other primary ovarian tumors. These data implicate SMARCA4 in SCCOHT oncogenesis.

  Dataset EGAD00001000850

• Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4

  Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is an extremely rare, aggressive cancer affecting children and young women. We identified germline and somatic inactivating mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 75% (9/12) of SCCOHT patients in addition to SMARCA4 protein loss in 82% (14/17) of SCCOHT tumors, but in only 0.4% (2/485) of other primary ovarian tumors. These data implicate SMARCA4 in SCCOHT oncogenesis.

  Dataset EGAD00001000794

• microRNA-seq of human serum from a longitudinal study of 66 women with no history of cancer

  This dataset includes microRNA sequencing data from 198 human serum samples, representing a subset of 66 women with no history of cancer who participated in the UKCTOCS study and with serum samples collected at three timepoints over a period of up to 5 years. Small RNA libraries prepared from the serum samples were sequenced with 50-bp single end reads on an Illumina HiSeq 2000 instrument. Data is provided as FASTQ files.

  Dataset EGAD00001004348

• Genomic Signatures Reveal DNA Damage Response Deficiency in Brain Metastases of Colorectal Cancer

  Brain metastasis (BM) of colorectal cancer (CRC) is rare but lethal and lacks effective therapies or a good understanding of its genomic landscapes. We conduct an analysis of whole-exome sequencing (WES, Illumina HiSeq 2500 sequencing platform) on 11 patient-matched BMs, primary CRC tumours, and adjacent normal tissues; and whole-genome sequencing (WGS, Illumina HiSeq X Ten platform) on 8 patient-matched BMs, primary CRC tumors, and adjacent normal tissues to uncover the whole-genome mutational landscape of colorectal cancer with brain metastasis.

  Dataset EGAD00001005030

• The effect of anti-HER2/CD3 TDB on transcription in human CD8 T cells (bulk RNA-seq)

  RNA was isolated from purified human CD8 cells that were incubated with anti-HER2/CD3 TDB in the presence of SK-BR-3 cells. Sequencing libraries were generated and submitted for transcriptome profiling by high-throughput sequencing. Experiments were performed in triplicates for anti-HER2/CD3 TDB treatment and control. This Dataset is associated with the following ArrayExpress Experiment: E-MTAB-8211 - The effect of anti-HER2/CD3 TDB on transcription in human CD8 T cells (bulk)

  Dataset EGAD00001005187

• MASQ targeted amplicon sequencing data of AML samples at presentation, remission, and relapse, and MASQ data demonstrating performance ranges of the method.

  MASQ targeted amplicon sequencing of AML blood or bone marrow at presentation, and relapse, when available, for 5 patients. Remission samples of both blood and bone marrow are included for 5 patients. Multiple batches (b1,b2) are used for 2 patients. There are 25 assays of AML data. MASQ data demonstrating sensitivity, input range, and batch size are also included, as 12 assays. All data is provided in paired FASTQ files.

  Dataset EGAD00001005121

• Phylogenetic development of childhood tumours

  The aim of this study is to reconstruct the phylogenetic development of childhood tumours

  Dataset EGAD00001005770

• Mapping genetic variants underlying gene regulation in healthy intestinal cell types to identify novel IBD drug targets (2020-05-12)

  Biopsies from the terminal ileum and rectum of healthy individuals are digested on ice to single cells and processed for single-cell RNA-sequencing (10X Genomics and Illumina) This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2020-05-12.

  Dataset EGAD00001006139

• Bottleneck Sequencing Of Human Tissue (Wgs) (2020-10-20)

  Bottleneck sequencing of human tissue including neurons, cord blood, sperm. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2020-10-20.

  Dataset EGAD00001006459

• Detection of ctDNA in Plasma of Patients with Clinically Localised Prostate Cancer is Associated with Rapid Disease Progression

  Whole genome sequencing of tumour-normal pairs in eight patients with clinically localised disease undergoing prostatectomy. A bespoke DNA capture and amplification panel against the highest prevalence, highest confidence aberrations for each individual was designed and used to interrogate ctDNA isolated from plasma prospectively obtained pre- and post- (24 hours and 6 weeks) surgery. Tagged-amplicon deep sequencing (TAm-Seq) across the TP53 gene in ctDNA in a cohort of 189 individuals.

  Dataset EGAD00001006369

• cell-free Nucleosome ChIP-seq

  Dataset includes cell-free ChIP-seq data of 268 samples (from 61 self-declared healthy donors, four patients with acute myocardial infarction, 29 patients suffering from autoimmune, metabolic, or viral liver diseases and 56 metastatic colorectal carcinoma (CRC) patients). DNA libraries preparation is documented in the methods section. Libraries were paired end sequenced by Illumina NextSeq 500 and aligned to the human genome (hg19) using bowtie2 (2.3.4.3) with ‘no-mixed’ and ‘no-discordant’ flags. This dataset includes fastq and BAM files of all samples.

  Dataset EGAD00001006811

• Oral microbiota composition assessed with 16S rRNA sequencing from adults aged over 65 years old.

  This is a oral microbiota amplicon dataset derived from adult participants aged over 65 years old. It consists a total number of 491 samples, stored in 982 paired-end FASTQ files with sequence lengths of 200 nucleotides generated with a Illumina MiSeq. Of those 491 samples, 347 were used in analysis, the remaining 144 samples are control samples.

  Dataset EGAD00001007705

• Single-cell RNA sequencing of T-LGLL patients

  Single-cell RNA sequencing was performed on viably frozen cells from 11 T-LGLL samples from 9 T-LGLL patients and 6 age-matched healthy samples. The raw data is available as fastq files.

  Dataset EGAD00001008409

• CPC-GENE primary prostate benign and tumour tissue Hi-C sequencing reads

  This dataset contains the raw sequencing data, in FASTQ format, for Hi-C assays from 17 primary prostate tissue samples. The sequencing data is paired-end, 150 bp sequencing data from an Illumina NovaSeq 6000 machine, and contains 5 benign tissue samples and 12 primary tumour samples from the Canadian Prostate Cancer Genome Network (CPC-GENE) project. Tumour samples have IDs starting with the "CPCG" prefix, and benign tissue samples have IDs starting with the "BP" suffix.

  Dataset EGAD00001008024

• WES of breast and larynx cancer cases

  The dataset is based on 37 FFPE samples obtained from 12 patients diagnosed with breast or larynx cancer, For each patient 3 sample types were obtained P - primary tumor, L - malignant lymph node and C - benign lymph node (control). For patient G46 two malignant lymph nodes were used. DNA isolated from all samples was subject to exome selection using Agilent SureSelect Human All Exon V7. The obtained material was sequenced using NovaSeq 6000 platform with 2x150 reads. The sequencing was conducted by Novogene company.

  Dataset EGAD00001009081

• Neuroblastoma WGS samples used for analysis of telomeric sequences

  Paired-end WGS data of 10 neuroblastoma patient samples (5 obtained at diagnosis and 5 matched blood samples as controls) used for analysis of telomeric content and sequence composition. Mean coverage is 11-65x per sample. The remaining patient samples of the dataset can be found under accession numbers EGAS00001001308 and EGAS00001005424 and mappings of the patients IDs in the supplementary material of the publication.

  Dataset EGAD00001009289

• RNAseq of primary mesothelioma cell lines

  Mesothelioma is an aggressive cancer associated with previous exposure to asbestos and dismal prognosis. Since a pemetrexed/cisplatin combination was introduced for treatment of mesothelioma, no new first- or second-line therapies have been discovered. Thus, to better understand what drives mesothelioma carcinogenesis and to identify potential targets for therapy, in this project we aim at performing RNAseq analysis of a panel of mesothelioma cells lines.

  Dataset EGAD00001009642

• Single-cell bam files and RNA sequencing of viral RNA stocks

  244 infected single-cell alveolar bam files, 48 empty well bam files, and 52 RNA sequencing of amplicons (4 SARS-CoV-2 variants with 12 batches and 4 viral variants pool samples). 244 alveolar single cells were captured over 12 experimental batches and experimental condition is written in metadata uploaded as "infected_cells_final_revision.csv". on github (https://github.com/twkim-0510/SARS-CoV-2_viral_competition). Each bam file name corresponds to the sample_name column of the metadata.

  Dataset EGAD00001009711

• scRNAseq and scATACseq of MMR vaccinattion

  Dataset containing 48 samples: 12 per timepoint (before or after treatment) and group (MMR vaccine or Placebo). Each sequencing run contains the sequencing data from 4 randomized samples. Genotype data is used to demultiplex sample ids inside of each pool. Phenotype data contains the information per pool.

  Dataset EGAD00001010012

• To profile the landscape of sebaceous tumours_WES

  Sebaceous tumours are a rare cutaneous cancer with potential for aggressive behaviour. However, limited information is available on these cancers with few published cases. Here we wish to exome sequence these cancers to define the first genomic landscape for this malignancy. We will extract DNA from formalin-fixed, paraffin-embedded (FFPE) cores. Cores may be obtained from lesional and non-lesional tissues of primaries as well as matching metastases. The extracted DNA will be used for exome sequencing. Please note that the dataset was last revised on October 16, 2025.

  Dataset EGAD00001015367

• Single-Cell RNA Sequencing of Terminal Ileal Biopsies Identifies Signatures of Crohn’s Disease Pathogenesis

  Biopsies from the terminal ileum of healthy individuals and terminal ileum of Crohns disease patients are collected and processed single cells and processed for single-cell RNA-sequencing using 10X Genomics 3' v3 and v3.1 and Illumina sequencing. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Dataset EGAD00001015692

• Mapping genetic variants underlying gene regulation in intestinal cell types to identify novel IBD drug targets

  Biopsies from the terminal ileum and rectum of healthy individuals and terminal ileum and blood from Crohns disease patients are collected and processed single cells and processed for single-cell RNA-sequencing using 10X Genomics 3 v3 and v3.1 and Illumina sequencing. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Dataset EGAD00001016069

• Research Program on Genes, Environment and Health (RPGEH)

  The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) is a resource developed to facilitate research on genetic and environmental factors on common diseases and healthy aging. The RPGEH resource links biospecimens, health surveys, and comprehensive electronic medical records on broadly consented adult members of Kaiser Permanente Medical Care Plan, Northern California Region (KPNC). KPNC is an integrated health care delivery system with a membership of approximately 3.3 million people in northern California. The membership of KPNC is representative of the general population in the 14 county area in which facilities are located, although extremes of income are underrepresented. At the end of 2013, the RPGEH resource included: (1) demographic and behavioral surveys from over 430,000 participants; (2) biospecimens (DNA, serum, plasma, and/or saliva) from over 204,000 participants, including over 13,000 pregnant women; (3) genome-wide genotype data (70 billion SNP genotypes) on over 100,000 participants, including the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort; and (4) the longitudinal electronic medical records of the participants. The RPGEH was developed beginning in 2005 at the Division of Research of Kaiser Permanente Northern California by Catherine Schaefer (Director), Neil Risch (Co-Director), Lisa Croen, Eric Jorgenson, Lawrence Kushi, Charles Quesenberry, Sarah Rowell, Carol Somkin, Stephen Van den Eeden, Larry Walter, and Rachel Whitmer. Funding of the RPGEH was provided to C. Schaefer (PI) and N. Risch (co-PI) by the Wayne and Gladys Valley Foundation, The Ellison Medical Foundation, the Robert Wood Johnson Foundation, Kaiser Permanente Northern California, and the Kaiser Permanente National and Regional Community Benefit Programs. The GERA cohort was funded by a grant from NIH to RPGEH and UCSF (RC2 AG036607; C. Schaefer and N. Risch, PIs). At the time of the award of the RC2 project in late 2009, the RPGEH had established a cohort of about 140,000 individuals who had answered a detailed survey, provided saliva samples for extraction of DNA, and given broad consent for the use of their data in studies of health and disease. Survey and Cohort Recruitment. Initially, the RPGEH developed electronic disease registries to enable identification of phenotypes, using algorithms applied to EMR data. In 2007, the RPGEH mailed a four page survey to 1.9 million adult (&#8805; 18 years old) members of KPNC who had been members for two years or more, to obtain data on demographic and behavioral factors complementary to the clinical data in the EMR. The survey materials included a cover letter introducing the RPGEH, a two page list of Frequently Asked Questions, and the survey, which included questions on demographic factors such as education, race-ethnicity, income and marital status, dietary factors, physical activity, smoking, and alcohol consumption, as well as reproductive history and reproductive health. Members whose electronic medical records indicated a preference for written communications in Chinese or Spanish received survey materials both in English and a Chinese or Spanish translation. Approximately 400,000 completed surveys were returned. Saliva Sample Collection. Beginning in July 2008, respondents to the survey were asked to sign and return a consent form and authorization for use and disclosure of protected health information. The consent form authorized broad use of biospecimens, survey data, and data from participants&#39; electronic health records for use in studies of genetic and environmental influences on health and disease. Respondents who returned completed consent forms were mailed (Oragene) saliva collection kits; more than 132,000 saliva samples were collected in two years. Completed saliva kits were scanned and archived in a temporary biorepository at the KPNC Division of Research. In late 2009, the RPGEH began collection of saliva samples from the California Men&#39;s Health Study (CMHS), a cohort that had been previously assembled in 2002-2003 and had been excluded from the RPGEH survey mailing with the intent of later adding CMHS participants to the assembled RPGEH cohort. The CMHS was developed to facilitate research on prostate cancer and other conditions in older men; the study protocol is described in Enger, et al., 2006. It enrolled and surveyed more than 40,000 men in KPNC, ages 45-69 years, who were members of KPNC during 2002-2003. CMHS men completed two mailed surveys with demographic and behavioral data similar to that of the RPGEH. The data on analogous variables were reconciled and integrated with the data derived from the RPGEH cohort for use in the RPGEH resource. By 2011, RPGEH collected approximately 15,400 saliva samples from men participating in the CMHS. RPGEH Access and Collaborations Website and Procedures. The RPGEH maintains a web portal for inquiries and applications for collaboration and access to data. The url is: https://rpgehportal.kaiser.org/. RPGEH has an application process and an Access Review Committee that reviews applications for collaboration and use. For more information, please contact RPGEH through the website.

  Study phs000788

• Biological Determinants of Peritoneal Dialysis Outcomes

  Peritoneal Dialysis (PD) is a technique for treating kidney failure where fluid is instilled into the body's peritoneal cavity. Fluid and solutes travel across the peritoneum, and this is critical to successful PD. Studies have shown that certain demographic and clinical variables explain a small part of the variability in baseline peritoneal solute transfer rate and water transfer function across the peritoneum. This study sought to identify the common genetic variants associated with the baseline peritoneal function in patients starting treatment with PD and change in function upon treatment with PD. This study has two specific aims: Aim 1: To identify and validate genetic loci that influence the peritoneal solute transfer rate (PSTR) at start of PD. Aim 2: To identify and validate genetic loci in pre-specified biologic pathways with change in peritoneal ultrafiltration capacity. This study incorporates data from participants' peritoneal solute transfer rate in their first ever peritoneal equilibrium test (PET) and changes in the transfer of water across the peritoneal membrane over time in a sub-group of participants, demographic information, and results from laboratory analysis of DNA, blood, and dialysate. This study comprises patient populations from pre-existing biorepositories in Europe, and prospectively enrolled participants in United States, Canada, United Kingdom, and Australia. Clinical data related to the participants' peritoneal solute transfer rate from their first ever Peritoneal Equilibrium Test (PET), demographic information, and change in ultrafiltration capacity over time, are correlated with various genetic markers of interest. For individuals enrolled prospectively, blood and dialysate were collected at the first study visit. Annually, subjects either underwent a PET as standard of care or perform an additional 4-hour dwell as part of the study. These subsequent measures were utilized to determine change in ultrafiltration capacity over time. Inclusion criteria included adults over the age of 20 who are able to provide consent and had a record of a PET within 6 months of starting PD. Subjects with missing outcome data and that did not pass genotyping QC were excluded. Genotyping was performed in two batches using the Illumina InfiniumOmni2-5-8v1-3_A1 array with 2,372,784 single nucleotide variants (SNVs) in the first batch (n=1957). The second genotyping batch (n=1053) was on the InfiniumOmni2-5-8v1-4_A1 array with 2,382,209 SNVs. Imputation was performed using the Michigan Imputation Server and the HRC1.1 genotype reference. The Institutional Review Board of the University of Washington has &#8220;dbGaP-certified&#8221; the consent forms used to enroll participants in Australia, Canada, and United States and the genotype-phenotype data from the participants (n=827) deposited in the public repository. Furthermore, it has been determined that under the EU-GDPR regulations, depositing data of participants enrolled in UK, Belgium, and Sweden (n=2,023) into dbGaP &#8220;serves no lawful purpose&#8221; as the consent form used for enrolling participants did not obtain explicit permission for depositing data in a public repository.

  Study phs002996

• National Institute on Aging (NIA) Long Life Family Study (LLFS)

  The Long Life Family Study (LLFS) is an international collaborative study of the genetics and familial components of exceptional survival, longevity, and healthy aging. Families were recruited through elderly probands (generally in their 90s) who self-reported on the survival history of their parents and siblings, and on the basis of this information, families which showed clustering of exceptional survival were recruited. [Specifically, a Family Longevity Selection Score (FLOSS) &#8805;7 was required. The FLOSS measures the average excess Observed lifespan over that Expected based upon lifetables, while adding a bonus term for still-living individuals. Thus FLOSS is a useful tool for scoring and selecting families for inclusion in a research study of exceptional survival (Sebastiani et al., 2009, PMID: 19910380)]. Probands resided in the catchment areas of four Field Centers (Boston University, Columbia University, University of Pittsburgh, and University of Southern Denmark). Recruited family members were phenotyped through extensive in-home visits by teams of technicians who traveled all over the USA and Denmark. Blood assays were centrally processed at a Laboratory Core (University of Minnesota) and protocols were standardized, monitored and coordinated through a Data Management Coordinating Center (Washington University). We examined and extensively phenotyped in all major domains of healthy aging, 4,953 individuals in 539 families through comprehensive in-home visits. Of these, 4,815 gave dbGaP sharing permission and had sufficient quantity/quality of DNA for GWAS genotyping. This large collection of families, selected on the basis of clustering for exceptional survival, is a unique resource for the study of human longevity and healthy aging. We estimate that less than 1% of the Framingham Heart Study (FHS) families (a roughly random population family sample) would meet the minimal entrance criteria for exceptional survival required in the LLFS (Sebastiani et al., 2009, PMID: 19910380). Thus, the least exceptional LLFS families show more clustering for exceptional longevity than 99% of the FHS families. Although the LLFS pedigrees were selected on the basis of longevity per se in the upper generation (and the generation above that), the children&#39;s generation have significantly lower rates of many major diseases and have better healthy aging profiles for many disease phenotypes (Newman et al., 2011, PMID: 21258136). The participants had their first in-person visit between 2006 and 2009. After that visit, they were contacted annually by telephone to update vital status, medical history, and general health. Between 2014 and 2017, willing participants completed a second in-person visit. The second visit followed the same protocols and centralized training as the first visit. During the second visit, a portable carotid ultrasound exam was added. Again, participants were continuously contacted annually for telephone follow-up during the period of the second in-person visit and after that. Annual telephone follow-ups currently ongoing, and plans for a third in-person visit are in progress.

  Study phs000397

• Acute Respiratory Distress Network (ARDSNet) Study 04 Assessment of Low Tidal Volume and Elevated End-Expiratory Volume to Obviate Lung Injury (ALVEOLI-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. BiospecimensAccess to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-ALVEOLI include Plasma and DNA. Please note that use of biospecimens in genetic research is subject to a tiered consent. Available Data Outcome data regarding organ failure free days are not available. Objectives The ARDS Network is a consortium of clinical centers and a coordinating center to design and test novel therapies for the treatment of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS). The ARDS Network 01/03 trials included an investigation of the efficacy and safety of Ketoconazole and Respiratory Management in the treatment of ALI and ARDS (KARMA). The Ketoconazole arm of the KARMA study was later stopped due to an inability to show efficacy. Participants continued to be randomized to the respiratory management arms of the study (ARMA), which compared two ventilator strategies: a tidal volume of 6 mL/kg versus 12 mL/kg. The LARMA phase of the study investigated the efficacy of Lisofylline and Respiratory Management. The objective of the ALVEOLI study was to compare clinical outcomes of participants with ALI and ARDS treated with a higher end-expiratory lung volume/lower FiO2 versus a lower end-expiratory lung volume/higher FiO2 ventilation strategy. The ALVEOLI study tested the hypothesis that mortality from ALI and ARDS would be reduced with a mechanical ventilation strategy designed to prevent lung injury from repeated collapse of bronchioles and alveoli at end-expiration. Background Most participants requiring mechanical ventilation for ALI and ARDS receive positive end-expiratory pressure (PEEP) of 5 to 12 cm of water. Higher PEEP levels may improve oxygenation and reduce ventilator-induced lung injury but may also cause circulatory depression and lung injury from overdistention. PEEP levels higher than traditional levels may reduce ventilator-induced lung injury by decreasing the proportion of nonaerated lung and higher PEEP levels may allow arterial-oxygenation goals to be met at a lower level of inspired oxygen (FiO2). Participants A total of 550 participants were randomized to receive mechanical ventilation with either lower or higher PEEP levels, which were set according to different tables of predetermined combinations of PEEP and fraction of inspired oxygen. Conclusions Participants with acute lung injury and ARDS who receive mechanical ventilation with a tidal-volume goal of 6 ml per kilogram of predicted body weight and an end-inspiratory plateau-pressure limit of 30 cm of water, clinical outcomes were statistically similar whether lower or higher PEEP levels are used. (Brower, et al., 1004; PMID: 15269312).

  Study phs003714

• Resuscitation Outcomes Consortium (ROC) Controlled Study of the Clinical Effectiveness of Automated Real-Time Feedback on CPR Process Conducted at a Subset of ROC Sites (CPR) (ROC-CPR-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: A substudy of the ROC PRIMED trial, the ROC CPR trial sought to investigate whether real-time audio and visual feedback during cardiopulmonary resuscitation (CPR) outside a hospital increases the proportion of participants who achieved prehospital return of spontaneous circulation.Background: Cardiopulmonary resuscitation is an essential link in the chain of survival for treating cardiac arrest. However, performance of CPR is highly variable both outside hospital and in hospital. Interruptions in chest compression, inadequate depth of chest compression, and high rates of ventilation adversely affect blood flow during chest compressions and can hinder resuscitation. Suboptimal CPR, particularly time spent without chest compressions (low chest compression fraction), can reduce survival of cardiac arrest patients.Current technology incorporated into a monitor-defibrillator can assess core components of CPR through the use of an accelerometer and impedance changes across the defibrillation electrodes. This technology can also provide real-time audiovisual feedback so that the rescuer is prompted to perform according to guideline specifications. Use of such feedback increases the likelihood of performing CPR in accordance with guidelines during training and simulation. Participants: There were 1586 participants: 771 treated without feedback and 815 with feedback.Design: CPR feedback was provided through proprietary Q-CPR software operating in the Philips MRx monitor-defibrillator. The feedback feature of the defibrillator includes audible voice prompts and visual messages on the monitor screen that are triggered when measured chest compressions or ventilation deviate from guidelines or are interrupted.The study was conducted in 21 emergency medical service (EMS) agencies at three ROC regions in the U.S. and Canada. Randomized treatment clusters, which ranged from individual emergency medical vehicles to groups of emergency agencies, were assigned to feedback-on or feedback-off treatments. Each cluster remained in its assigned mode for two to seven months, after which it switched to the opposite treatment arm. At the end of those two treatment periods, each cluster was again randomly assigned to feedback-on or feedback-off. This cycle continued for the duration of the study. Each cluster switched treatment arms at least once, and up to four times, during the study. Conclusions: Real-time visual and audible feedback during CPR altered performance to more closely conform with CPR guidelines. Clusters assigned to feedback were associated with increased proportion of time in which chest compressions were provided, increased compression depth, and decreased proportion of compressions with incomplete release. However, frequency of prehospital return of spontaneous circulation did not differ according to feedback status, nor did the presence of a pulse at hospital arrival, survival to discharge, or awake at hospital discharge (Hostler, et al., 2011, PMID: 21296838).

  Study phs003818

• Resuscitation Outcomes Consortium Pragmatic Trial of Airway Management in out-of-Hospital Cardiac Arrest (ROC PART-BioLINCC)

  Data Access NOTE: Please refer to the &#8220;Authorized Access&#8221; 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 an initial airway management strategy using laryngeal tube (LT) insertion, compared with endotracheal intubation (ETI), on survival among adults with out-of-hospital cardiac arrest (OHCA).Background: Out-of-hospital cardiopulmonary arrest (OHCA) affects more than 350,000 adults in the United States each year, with only a low percentage of patients surviving to hospital discharge. Emergency medical services (EMS) paramedics commonly perform ETI or insertion of supraglottic airways (SGAs), such as the LT, on patients with OHCA to facilitate oxygenation and protect the lungs from aspiration of vomitus. Because SGA insertion is rapid, simple, and requires less training compared to ETI, many EMS agencies have incorporated this as the primary method of ventilation during OHCA resuscitation. However, the optimal method for OHCA advanced airway management is unknown.Participants: A total of 3004 patients were included; 1505 assigned to initial LT and 1499 assigned to initial ETI.Design: PART was a multicenter cluster-crossover randomized trial. The trial included 27 EMS agencies associated with US sites of the Resuscitation Outcomes Consortium (ROC). The EMS agencies were grouped into 13 randomization clusters. Each cluster selected a crossover interval of 3 or 5 months. Within each cluster, treatment assignments for consecutive intervals were computer-randomized in blocks of 2 to ensure balanced exposure to both airway groups. Crossovers between study groups could occur more than once. Treatment assignments were initial LT insertion or initial ETI. Neuromuscular blocking agents or video laryngoscopy was permitted for initial intubation efforts. The trial did not limit the number of initial LT insertion or ETI attempts. If the initial insertion efforts were unsuccessful, EMS personnel performed rescue airway management using any available airway technique. EMS personnel followed local protocols for confirmation of airway placement and management of OHCA, including field termination of resuscitation efforts. Patients receiving bag-valve mask (BVM) ventilation only were retained in their assigned treatment group per intention-to-treat principles. The trial did not prescribe clinical care at the receiving hospitals, including use of EMS airway, targeted temperature management, percutaneous coronary intervention, or the timing of withdrawal of life-sustaining therapy.The primary outcome was 72-hour survival. Secondary outcomes included return of spontaneous circulation, survival to hospital discharge, and favorable neurological status at hospital discharge (Modified Rankin Scale score &#8804;3). Conclusions: Among adults with OHCA, a strategy of initial LT insertion was associated with significantly greater 72-hour survival compared with a strategy of initial ETI. These findings suggest that LT insertion may be considered as an initial airway management strategy in patients with OHCA, but limitations of the pragmatic design, practice setting, and ETI performance characteristics suggest that further research is warranted.

  Study phs003902

• NHLBI Recipient Epidemiology Donor Evaluation Study (REDS)-III - Red Blood Cell Omics (RBC-Omics) Study

  The Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) is an initiative launched by the National Heart, Lung, and Blood Institute (NHLBI) with the goal to improve transfusion medicine practice, ensure safety and reduce risks. Extensive variation exists in donor iron metabolism, hemoglobin production, and hemolysis. Despite this variation, current blood banking guidelines regulating blood donation frequency, donation volume, and storage time and conditions remain uniform for all donors. The RBC-Omics study proposed to investigate if this approach is appropriate. Specifically, the RBC-Omics study: Established a multi-ethnic cohort of blood donors with well-characterized demographic, behavioral, and donation history. Developed a database linking donations from these blood donors to outcomes in transfusion recipients. Identify genetic factors impacting hemoglobin, donation history, ferritin, and iron metabolism. Identify markers and clinical factors associated with the iron-related disorders pica and restless leg syndrome (RLS). Define the genetic and metabolic basis for donor-specific differences in spontaneous, osmotic and oxidative hemolysis at the end of storage. RBC-Omics study has 13,403 blood donors over the age of 18 that were recruited from December 2013 to December 2015 at four REDS-III blood centers: the American Red Cross (Farmington, CT), the Institute for Transfusion Medicine (ITxM, Pittsburgh, PA), Blood Center of Wisconsin (Milwaukee, WI), and the Blood Centers of the Pacific (San Francisco, CA). All blood donors are healthy volunteers who passed donation screening and were not anemic. The samples were genotyped with a customized Affymetrix Axiom array called the TM-Array. The TM-array was specifically designed to cover genetic variations related to transfusion medicine. Also copy number polymorphisms in the alpha globin, beta globin and Rh gene clusters were added. The genetic variations among different ethnicity groups were considered as well.

  Study phs001955

• Shanghai Breast Cancer Genetics Study (SBCGS)

  The Shanghai Breast Cancer Genetics Study (SBCGS) includes data from four population-based studies conducted among Chinese women in urban Shanghai: the Shanghai Breast Cancer Study (SBCS), the Shanghai Breast Cancer Survival Study (SBCSS), the Shanghai Women&#39;s Health Study (SWHS), and the Shanghai Endometrial Cancer Study (SECS, contributing controls only). Shanghai Breast Cancer Study (SBCS): The SBCS is a population-based, case-control study conducted in urban Shanghai. Subject recruitment in the initial phase of the SBCS (SBCS-I) was conducted between August 1996 and March 1998. The second phase (SBCS-II) of recruitment occurred between April 2002 and February 2005. Breast cancer cases were identified through the population-based Shanghai Cancer Registry and supplemented by a rapid case-ascertainment system. Controls were randomly selected using the Shanghai Resident Registry. Approximately 3500 cases and 3500 controls were recruited in the study. Shanghai Breast Cancer Survival Study (SBCSS) and Shanghai Endometrial Cancer Study (SECS): The SBCSS also used the population-based Shanghai Cancer Registry to identify newly diagnosed breast cancer cases. A total of 5,046 breast cancer patients were recruited. In-person interviews were conducted to collect information on known breast cancer risk factors and anthropometrics by using protocols and questionnaires similar to those used in the SBCS. For genetic studies, controls for the SBCSS cases came from the SECS, which recruited healthy women between January 1997 and December 2003. With the exception of a few questions related specifically to breast or endometrial cancer risk, the questionnaires used in the SECS and the SBCS were very similar. Shanghai Women&#39;s Health Study (SWHS): The SWHS is a population-based prospective cohort study of approximately 75,000 adult women who were recruited between 1997 and 2000. The cohort has been followed by a combination of record linkage and active follow-ups. Breast cancer patients identified in the SWHS and non-cases were included in the current study.

  Study phs001088

• Polycystic Ovary Syndrome (PCOS) Genetics

  PCOS is a complex genetic disease reflecting the interplay of susceptibility genes and environmental factors. The cardinal reproductive feature of the syndrome, hyperandrogenemia, appears to play a direct role in the pathogenesis of the associated metabolic abnormalities. Male as well as female first-degree relatives have reproductive and metabolic phenotypes including increased prevalence rates of type 2 diabetes (T2D), metabolic syndrome (MBS) and other risk factors for cardiovascular disease (CVD). Northwestern University (NU) investigators lead a team that has extensive experience in phenotyping PCOS and in the genetic analysis of complex diseases including genome-wide association study (GWAS). Together with an expert group of collaborators from the Hershey Medical Center, and The University of Chicago, we have conducted a GWAS to identify PCOS susceptibility alleles using a large cohort of extensively and consistently phenotyped PCOS cases. Population controls for this study come from the NUgene project described below. NUgene project: In 2002, Northwestern committed to the development of a DNA repository to serve as a platform for the identification and validation of genotype-phenotype associations that will impact healthcare. The NUgene Project is a repository with longitudinal medical information from participating patients at affiliated hospitals and outpatient clinics from the Northwestern University Medical Center. Participants&#39; DNA samples are coupled with data from a questionnaire (2 versions were used, 1 before and 1 after February 2006, both are included) and continuously updated data from our Electronic Medical Record (EMR) representing actual clinical care events. Northwestern has a state-of-the art, comprehensive inpatient and outpatient EMR system of over 2 million patients. NUgene has broad access to participant data for all outpatient visits as well as inpatient data via a consolidated data warehouse. NUgene participants consent to distribution and use of their coded DNA samples and data for a broad range of genetic research by third-party investigators.

  Study phs000368

• A Genome-Wide Association Study of Sporadic ALS in an Irish Population (SIALS) and Sequencing and Analysis of an Irish Human Genome

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motor neurons. Epidemiological studies indicate that 2-5% of cases are familial, usually with an autosomal dominant pattern of inheritance. For a portion of these, causative genes have been identified. The remaining 95% of ALS cases are described as sporadic, and believed to result from a combination of genetic and environmental factors. This study utilized samples from Irish patients with sporadic ALS and Irish control individuals. The aim of the study was to identify susceptibility alleles for ALS in the Irish population. Genome-wide, single-nucleotide polymorphism (SNP) genotyping was undertaken using Illumina 550K version 3 chips. Genotyping data are available on 221 SALS patients and 211 controls. Future work will aim to examine ALS genetic risk at individual sequence level. As an initial step, as of September 2010 we have made available the human genome sequence from a single anonymous male control individual from the SIALS collection. Recent studies generating complete human sequences from Asian, African and European subgroupings have revealed population specific variation and illuminated disease susceptibility loci. The Irish population is of interest because of its location at the periphery of Europe and also the impact its emigrants have had on the genetics of populations in a number of other countries. We have identified sequence variants that may be specific to this population and have identified potentially novel disease associated variants. We describe a novel method for improving SNP calling accuracy at low genome coverage using haplotype information. Overall we demonstrate utility in generating whole genome sequences to test general principles and reveal specific instances of human biology. With increasing access to low cost sequencing we would predict that similar studies will emerge.

  Study phs000127

• Shanghai Breast Cancer Genetics Study (SBCGS)

  The Shanghai Breast Cancer Genetics Study (SBCGS) includes data from four population-based studies conducted among Chinese women in urban Shanghai: the Shanghai Breast Cancer Study (SBCS), the Shanghai Breast Cancer Survival Study (SBCSS), the Shanghai Women&#39;s Health Study (SWHS), and the Shanghai Endometrial Cancer Study (SECS, contributing controls only). Shanghai Breast Cancer Study (SBCS): The SBCS is a population-based, case-control study conducted in urban Shanghai. Subject recruitment in the initial phase of the SBCS (SBCS-I) was conducted between August 1996 and March 1998. The second phase (SBCS-II) of recruitment occurred between April 2002 and February 2005. Breast cancer cases were identified through the population-based Shanghai Cancer Registry and supplemented by a rapid case-ascertainment system. Controls were randomly selected using the Shanghai Resident Registry. Approximately 3500 cases and 3500 controls were recruited in the study. Shanghai Breast Cancer Survival Study (SBCSS) and Shanghai Endometrial Cancer Study (SECS): The SBCSS also used the population-based Shanghai Cancer Registry to identify newly diagnosed breast cancer cases. A total of 5,046 breast cancer patients were recruited. In-person interviews were conducted to collect information on known breast cancer risk factors and anthropometrics by using a protocol and questionnaire similar to those used in the SBCS. For genetic studies, controls for the SBCSS cases came from the SECS, which recruited healthy women between January 1997 and December 2003. With the exception of a few questions related specifically to breast or endometrial cancer risk, the questionnaires used in the SECS and the SBCS were very similar. Shanghai Women&#39;s Health Study (SWHS): The SWHS is a population-based prospective cohort study of approximately 75,000 adult women who were recruited between 1997 and 2000. The cohort has been followed by a combination of record linkage and active follow-ups. Breast cancer patients identified in the SWHS and non-cases were included in the current study.

  Study phs000799

• Mechanism and Response of Thymoglobulin in Patients with Myelodysplastic Syndrome (MDS)

  In people with MDS, the bone marrow stops making healthy blood cells and instead produces poorly functioning, malformed, and immature blood cells. This can lead to anemia resulting from too few healthy red blood cells, infection resulting from too few healthy white blood cells, and bleeding resulting from too few healthy platelets. The exact cause of MDS remains unknown, but it may be caused by abnormal autoimmune activity in which activated T cells, a type of white blood cell, prevent normal bone marrow production. ATG, a medication that inhibits immune function, can restore normal blood production in some people with MDS, but it is not known how this happens and why it does not happen in all MDS patients. The purpose of this study is to examine the effects of ATG in adults with MDS and to determine which individuals with MDS are most likely to benefit from treatment with ATG. Based on disease severity and likely disease progression, participants will be separated into either a high-risk group or a low-risk group. Participants will be hospitalized for a 4-day period during which they will receive daily infusions of ATG. Oral prednisone will be given 2 days before hospitalization, throughout hospitalization, and then for 14 days after hospitalization to limit the side effects of ATG. Antihistamines and acetaminophen will also be given during hospitalization to reduce the chances of an allergic reaction to ATG. After discharge, all participants will attend monthly study visits that will include blood collection, review of disease symptoms, and evaluation of medication response. At Week 16, participants in the high-risk group will undergo additional blood collection, a bone marrow biopsy, and a thorough evaluation of disease progression and the effects of MDS on daily living abilities. Participants in the low-risk group will undergo these same procedures at Week 24. Follow-up for all participants may last up to 2 years.

  Study phs000697

• NHLBI GO-ESP: Family Studies (Hematological Cancers)

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. Two major goals in the study of human malignancies are (i) to understand the genetic basis that underlies the predisposition of certain individuals to develop cancer and (ii) to identify the full spectrum of acquired mutations that occur in human cancers. There has been some progress in both of these areas with respect to hematologic malignancies but much remains to be discovered. As a result of recent advantages in sequencing technologies it is now feasible to sequence multiple individual whole exomes at reasonable cost. Such technologies provide a unique opportunity to transform our understanding of the biological basis of human cancer and to identify inherited genetic variants that predispose individuals to the development of hematologic malignancies. Myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS) and acute leukemia are clonal disorders of hematopoieis. Our study involves performing whole exome sequencing of individuals with these disorders for the purpose of identifying (i) novel inherited genetic variants associated with the risk of developing of MPN/MDS/acute leukemia and (ii) novel acquired mutations associated with the development of MPN/MDS/acute leukemia.

  Study phs000632

• Cardiovascular Health Study (CHS) Cohort: an NHLBI-funded observational study of risk factors for cardiovascular disease in adults 65 years or older

  The Cardiovascular Health Study (CHS) is a prospective study of risk factors for development and progression of CHD and stroke in people aged 65 years and older. The 5,888 study participants were recruited from four U.S. communities and have undergone extensive clinic examinations for evaluation of markers of subclinical cardiovascular disease. The original cohort, enrolled in 1989-90, totaled 5,201 participants. A supplemental cohort of 687 predominantly African-American participants was enrolled in 1992-93. Clinic examinations were performed at study baseline and at annual visits through 1998-1999, and again in 2005-2006. Examination components included medical and personal history, medication inventory, ECG, blood pressure, anthropometry, assessment of physical and cognitive function, and depression screening. Other components done less frequently included phlebotomy, spirometry, echocardiography, carotid ultrasound, cerebral magnetic resonance imaging, measurement of ankle-brachial index and retinal exam. Participants were contacted by telephone annually between exams to collect information about hospitalizations and potential cardiovascular events. Since 1999, participants have been contacted every six months by phone, primarily to identify cardiovascular events and to assess physical and cognitive health. Standard protocols for the identification and adjudication of events were implemented during follow-up. The adjudicated events are myocardial infarction, angina, heart failure (HF), stroke, transient ischemic attack (TIA), claudication and mortality. The Cardiovascular Health Study Cohort is utilized in the following dbGaP substudies. To view genotypes, analysis, expression data, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" section of this top-level study page phs000287 Cardiovascular Health Study (CHS) Cohort: an NHLBI-funded observational study of risk factors for cardiovascular disease in adults 65 years or older. phs000226 STAMPEED: Cardiovascular Health Study (CHS) phs000301 PAGE: CaLiCo: Cardiovascular Health Study (CHS) phs000377 CARe: Candidate Gene Association Resource (CARe) phs000400 GO-ESP: Heart Cohorts Exome Sequencing Project (CHS) phs000667 CHARGE: Cardiovascular Health Study (CHS)

  Study phs000287

• Direct Transposition of Native DNA for Sensitive Multimodal Single-Molecule Sequencing

  STUDY GOALS: This study focuses on elucidating the epigenetic modulators of prostate cancer progression and metastasis at high resolution. This is achieved by applying a novel, high-sensitivity single molecule sequencing assay that measures chromatin state on single DNA molecules (SMRT-Tag) to matched primary and metastatic tumor samples from the same patient. Samples are obtained from patient derived xenograft (PDX) models. STUDY DESIGN: Individuals diagnosed with primary and metastatic prostate cancer in the course of routine care were consented and enrolled, and biopsies of primary and/or metastatic lesions performed to obtain sample material used for generating PDX models. Samples collected from these models were processed with a novel strategy developed for highly-sensitive multimodal profiling of single chromatin fibers using the third generation long-read sequencing. The resulting data indicates genetic variants, chromatin organization, and m5dCpG methylation status across the genome. PRINCIPLE FINDINGS: We determined characteristic single-molecule patterns of chromatin organization (spacing of nucleosomes, presence and absence of m5dCpG marks, etc.) that were altered in the transition from primary malignancy to metastasis. Broadly, global chromatin organization was severely disrupted in metastatic samples, resulting in increased accessibility at CTCF motifs, which may be relevant for disease progression. We further identified specific genomic domains including constitutive heterochromatin significantly enriched for irregular or hyper-accessible chromatin. Together, these findings suggest the involvement of ATP-dependent chromatin remodelers in evicting nucleosomes as a facet of metastatic prostate cancer. DATA AVAILABILITY: SAMOSA-Tag, the assay used in this study, is a sequencing assay that uses the third generation long read sequencing, specifically the SMRT sequencing platform from Pacific Biosciences. Demultiplexed raw SMRT sequencing BAM files generated in this study are deposited. Individual raw subread BAM files correspond to replicate sequencing assays performed on either primary or metastatic PDX prostate tumors.

  Study phs003511

• 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

• Genomic features of Helicobacter pylori-na��ve diffuse-type gastric cancer.

  Helicobacter pylori (HP) is a major etiologic driver of diffuse-type gastric cancer (DGC). However, improvements in hygiene have led to an increase in the prevalence of HP-na��ve DGC; that is, DGC that occurs independent of HP. Although multiple genomic cohort studies for gastric cancer have been conducted, including studies for DGC, distinctive genomic differences between HP-exposed and HP-na��ve DGC remain largely unknown. Here, we employed exome and RNA sequencing with immunohistochemical analyses to perform binary comparisons between 36 HP-exposed and 27 HP-na��ve DGCs from sporadic, early-stage, and intramucosal or submucosal tumor samples. Among the samples, 33 HP-exposed and 17 HP-na��ve samples had been preserved as fresh-frozen samples. HP infection status was determined using stringent criteria. HP-exposed DGCs exhibited an increased single nucleotide variant burden (HP- exposed DGCs; 1.97 [0.48���7.19] and HP-na��ve DGCs; 1.09 [0.38���3.68] per megabase; p=0.0003) and a higher prevalence of chromosome arm-level aneuploidies (p&lt;0.0001). CDH1 was mutated at similar frequencies in both groups, whereas RHOA���ARHGAP pathway misregulation was exclusive to HP-exposed DGCs (p=0.0167). HP-exposed DGCs showed gains in chromosome arms 8p/8q (p&lt;0.0001), 7p (p=0.0035) and 7q (p=0.0354), and losses in 16q (p=0.0167). Immunohistochemical analyses revealed a higher expression of intestinal markers such as CD10 (p&lt;0.0001) and CDX2 (p=0.0002) and a lower expression of the gastric marker, MUC5AC (p=0.0305) among HP-exposed DGCs. HP-na��ve DGCs, on the other hand, had a purely gastric marker phenotype. This work reveals that HP-na��ve and HP-exposed DGCs develop along different molecular pathways, which provide a basis for early detection strategies in high incidence settings.

  Study JGAS000575

• ImmunAID

  The ImmunAID study is a multi-center research program aimed at improving the diagnosis and understanding of systemic autoinflammatory diseases. The study integrates immunological, and molecular data from patients across several European cohorts. Its objective is to identify biomarkers and biological pathways that characterize disease mechanisms and help differentiate between inflammatory conditions. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779295. The project has generated genomic datasets, which are available through the European Genome-phenome Archive (EGA). In addition, it has produced several non-genomic datasets, listed below. All datasets have been fully anonymized in accordance with applicable ethical and regulatory frameworks. These non-genomic data are available upon request. To request access to these datasets, please contact: immunaid2024@gmail.com Your request will be studied by the Data Access Committee, and data will be made available upon approval. Non-genomic datasets available: Flow cytometry (general immune phenotype) — Dataset ID: ICKD2021569, size: 23 GB, 342 patients Somascan proteomics data — Dataset ID: ICKD2021570, size: 59 MB, 444 patients ELISA panel (Ferritin, CRP, HO1, IL-1B, IL-6, IL-8, IL-10, IL-12, IL-18, IFN-γ, TNF-α) — Dataset ID: ICKD2021571, size: 295 KB, 439 patients Mass spectrometry (MS/MS) — Dataset ID: ICKD2021572, size: 1.8 TB, 447 patients ELISA (CRP/ SAA) — Dataset ID: ICKD2021573, size: 321 KB, 443 patients Flow cytometry (inflammasome activity) — Dataset ID: ICKD2021574, size: 899 KB, 307 patients Plasma lipidomics — Dataset ID: ICKD2021575, size: 1.1 MB, 427 patients Urine lipidomics — Dataset ID: ICKD2021576, size: 833 KB, 368 patients ELISA (alarmins) — Dataset ID: ICKD2021577, size: 129 KB, 108 patients ELISA (IL-18 / IL-1) — Dataset ID: ICKD2021578, size: 271 KB, 330 patients Flow cytometry (NK cell alterations) — Dataset ID: ICKD2021579, size: 14 GB, 216 patients Chemokine measurements — Dataset ID: ICKD2021580, size: 489 KB, 404 patients Luminex (multiple analyte measurements) — Dataset ID: ICKD2021581, size: 759 KB, 369 patients

  Study EGAS50000001393

• Dynamics of multiple resistance mechanisms in plasma DNA and their clinical implications for NSCLC patients receiving EGFR-targeted therapies

  Background:The development of resistance mechanisms to targeted therapies is complicated by underlying tumour heterogeneity. When multiple resistance mechanisms co-exist, identifying the dominant driver(s) is critical for selection of treatment. Patients and methods:We studied the relative dynamics of multiple oncogenic drivers and resistance mechanisms in 50 patients with EGFR-mutant non-small cell lung cancer (NSCLC), during treatment with gefitinib and hydroxychloroquine (NCT00809237). We performed digital PCR and targeted deep sequencing of cell-free DNA from longitudinal plasma samples from all patients, and shallow whole genome sequencing of serial samples from three patients who underwent histological transformation to small-cell lung cancer (SCLC). ResultsEGFR activating mutations were assessed in tumour samples and accurately identified in plasma samples of 95% of patients (41/43). We identified additional mutations including EGFR T790M (31/50, 62%), TP53 (23/50, 46%), PIK3CA (7/50, 14%), and PTEN (4/50, 8%), and tracked their relative levels in plasma. Patients with both TP53 and EGFR mutations detected in plasma pre-treatment tended to have worse overall survival than those where only EGFR was detected. The resistance-conferring EGFR T790M mutation was identified in 62% of the patients who progressed. Changes in relative levels of T790M and activating mutations in EGFR corresponded to clinical responses in two patients who were given sequential treatments. Patients who progressed without T790M detected in plasma had worse PFS during TKI continuation, and developed alternative resistance mechanisms, that could be identified in plasma DNA, including SCLC-associated copy number changes and TP53 mutations, that tracked with progression and response to subsequent therapies. Conclusion:Longitudinal analysis of multiple oncogenic drivers in ctDNA may help identifying dominant mechanisms of resistance to EGFR-targeted therapies, and highlight the importance of monitoring genetic events that are not direct drug targets but provide non-invasive molecular information that may guide clinical management.

  Study EGAS00001002908

• Same-day genomic and epigenomic diagnosis of brain tumors using realtime nanopore sequencing

  Molecular classification of cancer has entered clinical routine to inform diagnosis, prognosis and treatment decisions. At the same time, new tumor entities have been identified that cannot be defined histologically. For central nervous systems tumors, the current World Health Organization classification explicitly demands molecular testing, e.g. for 1p/19q- codeletion or IDH mutations, to make an integrated histomolecular diagnosis. However, a plethora of sophisticated technologies is currently needed to assess different genomic and epigenomic alterations and turnaround times are in the range of weeks, which makes standardized and widespread implementation difficult and hinders timely decision making. Here, we explored the potential of a pocket-size nanopore sequencing device for multimodal and rapid molecular diagnostics of cancer. Low-pass whole genome sequencing was used to simultaneously generate copy number (CN) and methylation profiles from native tumor DNA in the same sequencing run. Single nucleotide variants in IDH1, IDH2, TP53, H3F3A and the TERT promoter region were identified using deep amplicon sequencing. Nanopore sequencing yielded ~0.1X genome coverage within six hours and resulting CN and epigenetic profiles correlated well with matched microarray data. Diagnostically relevant alterations, such as 1p/19q codeletion, and focal amplifications could be recapitulated. Using ad hoc random forests, we could perform supervised pan-cancer classification to distinguish gliomas, medulloblastomas and brain metastases of different primary sites. Single nucleotide variants in IDH1, IDH2 and H3F3A were identified using deep amplicon sequencing within minutes of sequencing. Detection of TP53 and TERT promoter mutations shows that sequencing of entire genes and GC-rich regions is feasible. Nanopore sequencing allows same-day detection of structural variants, point mutations and methylation profiling using a single device with negligible capital cost. It outperforms hybridization-based and current sequencing technologies with respect to time-to diagnosis and required laboratory equipment and expertise, aiming to make precision medicine possible for every cancer patient, even in resource restricted settings.

  Study EGAS00001002213

• Short and long-read genome sequencing methodologies for somatic variant detection; genomic analysis of a patient with diffuse large B-cell lymphoma

  Recent advances in throughput and accuracy mean that the Oxford Nanopore Technologies (ONT) PromethION platform is a now a viable solution for WGS. New bioinformatic methods have been developed to take advantage of this long read data, however much of the validation of these tools has focussed on calling germline variants (both SNVs and structural variants). Somatic variants are outnumbered many-fold by germline variants and their detection is further complicated due to their frequency varying depending on tumour purity/subclonality. Here, we evaluate the extent to which Nanopore WGS enables genome-wide detection and analysis of somatic variation. We do this through sequencing tumour and germline genomes for a patient with diffuse B-cell lymphoma. We examine the capability of currently available tools for calling somatic variants in ONT data by comparing the data with results from 150bp short-read sequencing of the same samples. We then conduct a detailed analysis of the performance of multiple long-read mappers and structural variant callers for calling large, somatic structural variants (SVs) in ONT data. Our protocol achieved yields of up to 96 mapped Gb per PromethION flow cell with average read lengths of ~5kb. Calling germline SNVs from these data achieved good specificity and sensitivity. However, results of somatic SNV calling highlight the need for the development of specialized joint calling algorithms. Our analysis of structural variants shows that the comparative performance of different tools varies significantly between SV types, and suggest long reads are especially advantageous for calling large somatic deletions and duplications. Finally, we highlight the utility of long reads for phasing clinically relevant variants by using the ONT data to confirm that a somatic 1.6Mb deletion and a p.(Arg249Met) mutation involving TP53 are oriented in trans.

  Study EGAS00001004266

• ctDNA to predict risk of progression and death after trifluridin/tipiracil therapy

  Background. Late-line treatment in metastatic colorectal cancer (mCRC) can improve the prognosis. However, not every patient has a benefit and may experience severe side effects. Thus, predictive/prognostic biomarkers are urgently needed. Despite many promising results, the role of circulating tumor DNA (ctDNA) analysis in trifluridin/tipiracil (FTD/TPI) treated mCRC patients is so far still elusive. Study design. This prospective non-interventional translational biomarker phase II study enrolled 30 metastatic CRC patients treated with FTD/TPI. The primary study aim was to identify a molecular biomarker to predict overall survival (OS) benefit upon FTD/TPI treatment. Methods. mCRC patients (60% male, 40% female) with FTD/TPI therapy were included. Molecular profiling in cell-free DNA from plasma was performed prior to treatment and on average 4, 8 and 12 weeks after FTD/TPI initiation. Tumor levels were assessed as the highest variant allele frequency (hVAF) and correlated with OS. Uni- and multivariate analyses for survival were performed with clinical variables. Multivariate analyses for survival and treatment efficacy were adjusted to age, gender and ECOG performance status. Results. Compared to previous data, our disease control rate of 30% was lower with a median OS of 8.1 months and a median PFS of 3.2 months. At baseline (BL) and the first two follow-ups (FU), a hVAF cut-off of 7.5% was most discriminative (BL HR 0.39 95% CI 0.16 - 0.98 P=0.0212, FU1 HR 0.30 95% CI 0.12 -0.77 P=0.0021, FU2 HR 0.23 95% CI 0.08-0.70 P=0.0004) whereas at the last follow-up the stratification was most pronounced at a 15% cut-off. An elevated hVAF trajectory over time was associated with a higher risk of death. Conclusion. ctDNA is detectable in a high proportion of mCRC patients. Changes in ctDNA levels are associated with survival among FTD/TPI therapy and may identify patients who benefit most from treatment in these late-stage disease.

  Study EGAS00001006883