14976 results for "cancer studies using rna-seq"

in 45.90 milliseconds.

• NSIGHT BabySeq Project

  The Genomic Sequencing for Childhood Risk and Newborn Illness (BabySeq Project) is a research study exploring the use of genomic sequencing in newborns. The National Institutes of Health is funding this study. Investigators enrolled 240 healthy infants and their parents from the Brigham and Women's Hospital (BWH) Well Newborn Nursery and 240 sick infants and their parents at Boston Children's Hospital (BCH) or the BWH Neonatal Intensive Care Unit (NICU). A small blood sample was taken from each infant and genome sequencing may have been performed. Whole-exome (WES) was performed at the Broad Institute. Six weeks later, the results were returned and explained. Over 12 months, the investigators studied the experiences of parents and pediatricians of infants who receive sequencing to help understand how best to use genomics in pediatric care. Parents were surveyed at four points over the 12 months after enrollment: baseline, immediately post-disclosure (approximately 6 weeks after enrollment), 3 months post-disclosure, and at 10 months post-disclosure. Primary outcome measures included: (1) downstream health care costs attributable to BabySeq Project disclosure measured as days of inpatient care; (2) Parents' distress using validated scales and a novel item assessing blame; (3) parent-child relationship using validated scales; (4) Parents' relationship using validated and novel measures of marital satisfaction; (5-9) downstream health care utilization attributable to BabySeq project disclosure measured as the number of health care provider visits, per-patient counts for number of medications at 10 months, number of emergency room visits, number of outpatient lab tests, and per-patient means for healthcare costs in U.S. dollars. A secondary outcome was whether there was a change in perceived utility toward genomic sequencing. Findings of BabySeq include: (1) interest in newborn genomic testing is high among parents of healthy children and the majority of couples had similar levels of interest; (2) parents reported several motivations to receive and reasons to decline adult-onset only results from newborn sequencing; (3) 88% of newborns had at least one recessive carrier variant that could be relevant to their parents' future reproductive planning; (4) 5% of babies had an atypical pharmacogenomic variant related to how they might process medications used in childhood; (5) parent surveys using validated measures showed no evidence that newborn genomic sequencing caused increased psychological distress, even if the baby had a disease risk identified; and (6) 11% of newborn babies in the study had unanticipated monogenic disease risks.

  Study phs002093

• LCCC1122: Defining the Triple Negative Breast Cancer Kinome Response to GSK1120212

  In this study the investigators looked at adaptive reprogramming impact on the kinome when a MEK inhibitor called GSK1120212 (trametinib) was administered in a "window of opportunity" trial. GSK1120212 is not yet approved by the FDA for use in breast cancer patients. The investigators gave GSK1120212 for a short period of time (one week) to examine MEK and the other kinase expression in cancer cells both before and after the study drug is given. The investigators gave this drug for research purposes only. The length of time it was given is not intended to treat cancer. Recently researchers at UNC developed a process that can comprehensively profile the majority of the individual kinases in the kinome and examine the impact on kinase expression of kinase inhibitors (Duncan et al, Cell 2012, PMID: 22500798). This can tell us which kinases need to be concurrently blocked to augment responsiveness and prevent acquired resistance so that the investigators can design the best combinations of kinase blocking drugs for triple negative breast cancer. This is especially important for individuals with triple negative breast cancer (TNBC) because there are no targeted drugs available that can block molecules that affect tumor growth. The investigators believe that kinase-blocking drugs have the potential to be a more effective treatment for people with TNBC. In this recently published study (Zawistowski et al, Cancer Discovery 2017, PMID: 28108460), TNBC patients treated with trametinib for 7 days resulted in a transcriptional response characterized by significant reprogramming of the tyrosine kinome, and this adaptive bypass response in human tumors was found to be similar to that seen in preclinical models including TNBC cell lines and mouse xenografts. In this study we also examined whether reprogramming differed between TNBC molecular subtypes, finding that basal-like and claudin-low human TNBC cells and mouse tumor subtypes had different adaptive transcriptional responses to MEK-ERK inhibition. Mechanistically we found that genome-wide enhancer remodeling drove the adaptive transcriptional response, suggesting that epigenetic approaches to reprogramming may be more durable than kinase inhibitor polypharmacology.

  Study phs001405

• National Institutes of Health The Cancer Genome Atlas (TCGA)

  The Cancer Genome Atlas (TCGA) is a comprehensive and coordinated effort to accelerate our understanding of the molecular basis of cancer through the application of genome analysis technologies, including large-scale genome sequencing. TCGA is a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), which are both part of the National Institutes of Health, U.S. Department of Health and Human Services. TCGA projects are organized by cancer type or subtype. Click here for a current list of cancer types selected for study in TCGA. Data from TCGA (e.g., gene expression, copy number variation and clinical information), are available via the Genomic Data Commons (GDC). Data from TCGA projects are organized into two tiers: Open Access and Controlled Access. Open Access data tier contains data that cannot be attributed to an individual research participant. The Open Access data tier does not require user certification. Data in Open Access tier are available in the TCGA Data Portal. Controlled Access data tier contains individual-level genotype data that are unique to an individual. Access to data in the Controlled Access data tier requires user certification through dbGaP Authorized Access. Controlled Access data types consist of the following: Individual germline variant data (SNP .cel files) Primary sequence data (.bam files), which are available at GDC Clinical free text fields Exon Array files (for Glioblastoma and Ovarian projects only) NOTE: TCGA strives to release most data in the open access tier. Individual genotype or sequence files are prominent exceptions. Commonly requested files such as descriptions of somatic mutations or clinical data are open access. Please go to this page: https://tcga-data.nci.nih.gov/docs/publications/ to access all data associated with TCGA tumor specific publications. The TCGA study is utilized in the following dbGaP substudies. To view genotypes and other molecular data collected in these substudies, please click on the following substudies below or in the "Substudies" section of this top-level study page phs000178 TCGA study. phs000854 Genome-wide Analysis of Noncoding Regulatory Mutations in Cancer

  Study phs000178

• Evolutionary Trajectories of Small Cell Lung Cancer under Therapy

  Small cell lung cancer (SCLC) is one of the deadliest human cancers with a five-years survival rate of less than 7%. The standard of care for extensive-stage SCLC consists of systemic treatment with platinum and etoposide, recently combined with PD-L1 immune checkpoint inhibitors (ICI). SCLC patients show high sensitivity to platinum-based chemotherapy, followed by rapid recurrence, which distinguishes SCLC from most human cancers. Unfortunately, second-line treatment with other chemotherapeutics or immunotherapy is only marginally effective, and patients ultimately succumb to their disease. We performed whole exome sequencing, whole genome sequencing and transcriptome sequencing of multiple tumor regions from 65 patients with SCLC. We determined tumor phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multi-region sequencing of 160 tumors from 65 patients, to thus decipher the evolutionary processes underlying the remarkable sensitivity of small cell lung cancer (SCLC) to chemotherapy.

  Study EGAS50000000169

• Whole-genome sequencing in 14 cases and whole-exome sequencing in 90 cases of Chinese ESCC

  Esophageal cancer is one of the most aggressive cancers and the sixth leading cause of cancer death worldwide1. Approximately 70% of the global esophageal cancers occur in China and over 90% histopathological forms of this disease are esophageal squamous cell carcinoma (ESCC)2-3. Currently, there are limited clinical approaches for early diagnosis and treatment for ESCC, resulting in a 10% 5-year survival rate for the patients. Meanwhile, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we show a comprehensive genomic analysis in 158 ESCC cases, as part of the International Cancer Genome Consortium (ICGC) Research Projects (http://icgc.org/icgc/cgp/72/371/1001734). We conducted whole-genome sequencing in 14 ESCC cases and whole-exome sequencing in 90 cases.

  Study EGAS00001001487

• Characterization and clinical relevance of the genomic alterations defining invasive lobular breast cancer

  Background: Invasive lobular breast cancer (ILBC) is the second most common histological subtype after ductal breast cancer (IDBC). In spite of significant clinical and pathological differences, ILBC is still treated as IDBC. Here, we aimed at identifying recurrent genomic alterations in ILBC with potential clinical implications.Methods: Starting from 630 ILBC primary tumors with a median follow up of 10 years, we interrogated oncogenic substitutions and indels of 360 cancer genes and genome-wide copy number alterations in 413 and 170 ILBC samples, respectively, and correlated those findings with clinical, pathological, and outcome features. The Cancer Genome Atlas database was used for comparison of frequency estimates.Results: Besides the high mutation frequency of CDH1 in 65% of the tumors, alterations in one of the three key genes of the PI3K pathway, PIK3CA, PTEN and AKT1, were present in more than half of the cases. ERBB2 and ERBB3 were mutated in 5.1 and 3.6% of the tumors. FOXA1 mutations and ESR1 copy number gains were detected in 9% and 25% of the samples. All these alterations were more frequent in ILBC than IDBC. The histological diversity of ILBC was associated with specific genomic alterations, such as enrichment for ERBB2 mutations in the mixed, non-classic subtype, and for ARID1A mutations and ESR1 gains in the solid subtype. Finally, ERBB2 and AKT1 mutations were associated with short-term risk of relapse, and chromosome 1q and 11p gain with increased and decreased breast cancer free survival, respectively.Conclusion: ERBB2, ERBB3 and AKT1 mutations represent high prevalence therapeutic targets in ILBC. FOXA1 mutations and ESR1 gains urgently deserve dedicated clinical investigation, especially in the context of endocrine treatment.

  Dataset EGAD00001001395

• A Tumour Organoid Biobank for Mapping Cancer Cell Vulnerabilities - WGS

  Whole genome sequencing data from cancer patient-derived organoids and their matched tumour tissue samples. Part of a study to include genomic and transcriptomic sequencing data, along with CRISPR screening data from cancer patient-derived organoids and matched tumour tissues. Some organoids were developed as part of the Human Cancer Models Initiative (HCMI) in collaboration with Cancer Research UK (CRUK). The study includes organoids derived from colorectal, oesophageal, ovarian, pancreatic, and stomach cancer samples.

  Dataset EGAD00001015469

• Transcriptome Sequencing of Cancer Cell Lines

  In this study we will sequence the transcriptome of Verified Cancer Cell lines. This will be married up to whole exome and whole genome sequencing data to establish a full catalog of the variations and mutations found.

  Dataset EGAD00001000359

• Genomic profiling of patient-derived xenografts and organoids in prostate cancer

  Dataset contains genomic sequencing of 87 samples (blood germline, normal prostate tissues, human tumors, PDOs and PDXs). Sequencing was performed by whole-exome sequencing or targeted sequencing of prostate cancer genes.

  Dataset EGAD00001006403

• CAIRO2 - Whole Exome Sequencing (WES)

  Long-term Survival Update and Extended RAS Mutational Analysis of the CAIRO2 Trial: Addition of Cetuximab to CAPOX/Bevacizumab in Metastatic Colorectal Cancer. Whole Exome Sequencing (WES) of 64 metastatic colorectal cancer (mCRC) from CAIRO2 trial. WES data was used for mutational analysis.

  Dataset EGAD50000001140

• CAIRO2 - Shallow Whole Genome Sequencing (sWGS)

  Long-term Survival Update and Extended RAS Mutational Analysis of the CAIRO2 Trial: Addition of Cetuximab to CAPOX/Bevacizumab in Metastatic Colorectal Cancer. Shallow Whole Genome Sequencing (sWGS) of 52 metastatic colorectal cancer (mCRC) samples from CAIRO2 trial. sWGS was used for mutational analysis.

  Dataset EGAD50000001141

• Whole-exome sequencing of breast cancer metastasis and corresponding blood samples

  Whole-exome sequencing (WES) of 216 breast cancer metastasis-normal pairs from patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA or MOSCATO prospective trials (France).

  Dataset EGAD00001002747

• whole genome sequencing data of genomic heterogeneity of multiple synchronous lung cancer.

  Fastq data of genomics heterogeneity of multiple synchronous lung cancer. Whole-genome sequencing (WGS) were performed in 3 tumour samples, one regional lymph node metastasis sample and peripheral blood sample from the same patient with MSLCs.

  Dataset EGAD00001003458

• Somatic mutations of 256 whole-genome sequenced colorectal cancer tumors.

  Somatic mutations of 256 whole-genome sequenced colorectal tumors. 234 MSS, 19 MSI and 3 POLE mutants. See Katainen R. et al. CTCF/cohesin-binding sites are frequently mutated in cancer, Nature Genetics 2015. doi:10.1038/ng.3335

  Dataset EGAD00001004329

• Metastatic breast cancer targeted gene screen (2014-09-24)

  The samples will be sequenced for a targeted panel of cancer relevant genes (n ~ 370) and analysed for somatic mutations. This dataset contains all the data available for this study on 2014-09-24

  Dataset EGAD00001001018

• WGS on patients 5-7, study of metastatic prostate cancer

  Data from the study of subclonal metastatic expansion in prostate cancer. Whole genome shotgun sequencing of six samples, tumour and whole blood, from the three additional patients whose somatic variants were examined in depth.

  Dataset EGAD00001001344

• There are 116 liver cancer cases in this study and belong to LICA-CN project.The NGS test was performed with whole exome sequencing with HiSeq 2000 platform.

  There are 116 liver cancer cases in this study and belong to LICA-CN project

  Dataset EGAD00001003174

• Metastatic breast cancer targeted gene screen (2017-05-11)

  The samples will be sequenced for a targeted panel of cancer relevant genes (n ~ 370) and analysed for somatic mutations. This dataset contains all the data available for this study on 2017-05-11.

  Dataset EGAD00001003330

• Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers

  To identify predictive biomarkers of response and resistance to platinum agents in PDX models of triple-negative breast cancer

  Study EGAS00001006393

• Variants from germline WES data of pediatric cancer patients

  This dataset contains germline variants (in .vcf format) from six pediatric cancer patients (sample IDs D1 - D6). WES data of the children and their parents was mapped to hg38. A consensus of four variant callers was used to obtain germline variants of the children.

  Dataset EGAD00001009678

• Hyperpolarized carbon-13 MRI for very early response assessment of neoadjuvant chemotherapy in breast cancer patients

  Transcriptomic data for five patients with breast cancer undergoing neoadjuvant chemotherapy and hyperpolarised 13C-MRI for early response assessment

  Dataset EGAD00001008141

• Breast cancer sequential sampling study

  This study aims to whole genome sequence DNA derived from breast cancer patients who received neo-adjuvany chemotherapy. All patients had multiple biopsies performed before chemotherapy. Patients who had residual disease after the course of treatment underwent a further biopsy. We aim to characterise the mutations involved.

  Dataset EGAD00001000387

• dataset for esophageal cancer, 17 pairs for whole-genome sequencing and 71 pairs for whole-exome sequencing

  dataset for esophageal cancer, 17 pairs for whole-genome sequencing and 71 pairs for whole-exome sequencing

  Dataset EGAD00001000760

• Cancer-Normal chronic myeloid leukaemia sequencing data for "A comparative analysis of algorithms for somatic SNV detection in cancer", Bioinformatics 29 (2013) 2223

  This dataset contains the fastq sequencing data collected from bone marrow DNA of a chronic myeloid leukaemia patient at time of diagnosis.

  Dataset EGAD00001000967

• Multi-region sequencing of a RET fusion positive cancer patient

  Deep WGS sequencing (160x) of 2 different sites of disease of a patient with a RET fusion positive cancer. Amplicon sequencing of 19 other sites of the same patients for the RET fusion.

  Dataset EGAD00001005776

• Somatic Genome Dynamics of Barrett's Esophagus Patients with Non-Cancer and Cancer Outcomes

  A case-control study was designed with 80 participants diagnosed with Barrett's Esophagus (BE) selected from a larger case-cohort study (Li et al., 2014, PMID: 24253313) within the Seattle Barrett's Esophagus Program (SBEP) at the Fred Hutchinson Cancer Research Center. The study included 40 cases with BE with non-cancer outcomes, "NCO", who did not progress to esophageal adenocarcinoma (EA), and 40 controls who progressed to an endoscopically detected, incident EA (cancer outcome, "CO"). For each patient, two timepoints were evaluated (T1 and T2). NCO were matched to CO based on age at T1 (T1=first endoscopy with sufficient sample availability), and time between T1 and T2 (T2 in CO=time of diagnosis of incident EA). In 10 NCO, a third time point (T3), a mean of 13.2 years after T1, was also sequenced. Mapped endoscopic biopsies, at 1/3 and 2/3 annotated distances from the gastroesophageal junction within the Barrett's segment, were sampled per patient at each timepoint. Each biopsy was purified to separate BE epithelium from stroma, and DNA was extracted from purified epithelium for 60X WGS and 2.5M SNP array; normal control blood (N=62) or normal gastric sample (N=18) were analyzed by 30X WGS and 2.5M SNP array. An additional seven normal gastric biopsy samples in seven patients with normal control blood were also sequenced at 60X as controls. All research participants contributing clinical data and esophageal samples to this study provided written informed consent, subject to oversight by the Fred Hutchinson Cancer Research Center IRB Committee D (Reg ID 5619).

  Study phs001912

• Oncogenome of Kaposi Sarcoma

  Kaposi Sarcoma (KS) is an aggressive cancer caused by the Kaposi Sarcoma Herpesvirus (KSHV/HHV-8). Individuals with immunodeficiencies, exemplified by HIV, have an elevated risk of developing KS. However, understanding of the genetic factors contributing to KS progression is still limited. To explore potential genetic alterations in KS that could offer biological or therapeutic insights, whole exome sequencing was performed on 78 KS tumors and matching normal skin samples from 59 adults with KS (46 with HIV-associated KS and 13 with HIV-negative KS) receiving treatment at the Uganda Cancer Institute in Kampala, Uganda. Results showed a very low mutational burden in all samples except one (median = 11 mutations), which is the smallest number of mutations found across all 33 cancer types in The Cancer Genome Atlas (TCGA). No recurrent mutations were identified. Mutational signatures included impaired DNA mismatch repair and smoking. There was no evidence suggesting that multiple tumors from the same patient originated from a single clone. The number of genome copy alterations per genome was higher in tumors from individuals without HIV and those with advanced-stage disease. This suggests that lesions that take longer to develop may accumulate more alterations, although the overall number of alterations remains low compared to other cancers. These findings suggest that KS pathogenesis differs from other cancers, with KSHV viral infection and the expression of viral oncogenes being the primary drivers of carcinogenesis, rather than clonal oncogenic transformation arising from genetic alterations of cancer-related cellular genes.

  Study phs003897

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

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

  Study EGAS00001002840

• Clinical Proteomic Tumor Analysis Consortium (CPTAC) Proteogenomic Confirmatory Study of Breast, Colon, Lung, and Ovarian Tumors

  Recently, significant progress has been made in characterizing and sequencing the genomic alterations in statistically robust numbers of samples from several types of cancer. For example, The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and other similar efforts are identifying genomic alterations associated with specific cancers (e.g., copy number aberrations, rearrangements, point mutations, epigenomic changes, etc.). The availability of these multi-dimensional data to the scientific community sets the stage for the development of new molecularly targeted cancer interventions. Understanding the comprehensive functional changes in cancer proteomes arising from genomic alterations and other factors is the next logical step in the development of high-value candidate protein biomarkers. Hence, proteomics can greatly advance the understanding of molecular mechanisms of disease pathology via the analysis of changes in protein expression, their modifications and variations, as well as protein-protein interaction, signaling pathways and networks responsible for cellular functions such as apoptosis and oncogenesis. Realizing this great potential, the NCI launched the second phase of the CPTC initiative in September 2011. Renamed the Clinical Proteomic Tumor Analysis Consortium, CPTAC is beginning to leverage its analytical outputs from Phase I to define cancer proteomes on genomically-characterized biospecimens. The purpose of this integrative approach is to provide the broad scientific community with knowledge that links genotype to proteotype and ultimately phenotype. The data contained in this dataset are derived from samples designed to confirm CPTAC findings from the TCGA samples. These confirmatory samples contain breast, ovarian, colon, and lung tumors collected via a protocol optimized for proteomics. Specifically, ischemic time of the sample was controlled and restricted to less than 30 minutes. ACGT, Inc. produced whole exome, mRNAseq, and miRNAseq for these samples. Corresponding proteomic data are available at: https://cptac-data-portal.georgetown.edu/cptacPublic/ The study design was to profile colon, breast, ovarian, and lung tumors both genomically and proteomically. Germline DNA was obtained from blood. Normal control samples for proteomics varied by organ site: adjacent colon tissue for colon cases, contralateral breast tissue for some breast cases, and Fallopian tube fimbria for some ovarian cases. Lung cases had no normal control for proteomic analysis. All cancer samples were derived from primary and untreated tumors.

  Study phs000892

• NCI CCSG CCDI Supplement Additional Genomic Submission

  The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. This supplement data from the Beat AML program provides Adolescent and Young Adult (AYA) and pediatric tumor specimens not previously released. These data include exome and RNA level characterization as well as analyses of ex vivo drug sensitivity. Collectively, this data can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of leukemia in pediatric and AYA populations.

  Study phs002599

• Novel APC Promoter and Exon 1B Deletion and Allelic Silencing in Three Mutation-Negative Classic Familial Adenomatous Polyposis Families

  The ~80% of individuals with classic familial adenomatous polyposis (FAP) have detectable mutations in the coding sequence of the adenomatous polyposis coli (APC) gene. To investigate the 20% of families without detectable causative mutations, we used exome sequencing and second-generation sequencing of the APC locus including non-coding regions. We identified a novel ~11kb deletion 44kb upstream of APC that was present only in affected individuals of three kindreds. SNP analysis showed that this ~11kb deletion was accompanied by silencing of one of the APC alleles in blood-derived RNA of affected individuals.

  Study phs000904

• Circulating RNAs in Acute Heart Failure (CRUCIAL)

  The purpose of this American Heart Association-funded and NIH-funded study is to examine circulating RNAs in the acute congestive heart failure (CHF) setting, and how they change with decongestive therapy, and their function in vitro and in vivo. The investigators are testing the hypothesis that ex-RNA levels change significantly during decongestion therapy and can be used as a marker of those individuals who respond to CHF therapy (in terms of cardiac structure or outcome). Additionally, the translational research design allows the investigators to assay the effects of these RNAs on tissue phenotypes in vitro.

  Study phs003403

• High-resolution profile of neoantigen-specific TCR activation links moderate stimulation to increased resilience of engineered TCR-T cells

  Neoantigen-specific T cell receptors (neoTCRs) promise safe, personalized anti-tumor immunotherapy. Previously, we identified diverse neoTCRs restricted to different neoantigens in a melanoma patient. In this work, we now combined single-cell TCR- and RNA-sequencing after neoantigen-specific restimulation of peripheral blood-derived CD8+ T cells of this patient. We detected novel neoTCRs with specificity to the previously detected neoantigens and observe a heterogeneous spectrum of TCR-intrinsic activation patterns in response to a shared neoepitope ranging from previously detected higher frequent neoTCRs with moderate activation to rare ones with initially stronger activation.

  Study EGAS50000000600

• Systematic Analysis of Transcription Program Regulation by Transcription Factor EB (TFEB)

  In order to evaluate the effects of TFEB, a master regulator of autophagy and lysosomal biogenesis, CRISPR-Cas9 TFEB knock out cell lines were generated and reconstituted with wild-type TFEB (TFEB-WT), a vector control (TFEB-KO) or TFEB engineered to remain localized to the cytosol (TFEB-cyto) or to the nucleus (TFEB-nuc). RNA sequencing was performed on engineered cell lines at steady-state or following exogenous stimulation with autophagy inducer (Torin1 or Salmonella bacterial infection). Comparative analyses were performed to identify TFEB-dependent transcriptional response to subcellular localization at steady-state or to exogenous stimuli.

  Study phs002099

• RNAseq profile of monomorphic epitheliotropic intestinal T-cell lymphoma and enteropathy associated T-cell lymphoma

  Background : Enteropathy-associated T-cell lymphoma (EATL) and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) are aggressive malignancies with limited treatment options and poor prognosis. Our research on MEITL has uncovered its genetic portrait including hallmark SEDT2 mutations, expanded its pathological spectrum, and identified molecular biomarkers influencing patients’ outcome. In this study, we aimed to establish and clarify the similar and diverging features of EATL. Methods : A large combined cohort of patients with EATL (n=30) and MEITL (n=52) was assembled and tumor samples were used for whole-exome and RNA sequencing profiling.

  Study EGAS50000001125

• Whole Exome Sequencing of monomorphic epitheliotropic intestinal T-cell lymphoma and enteropathy associated T-cell lymphoma

  Background : Enteropathy-associated T-cell lymphoma (EATL) and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) are aggressive malignancies with limited treatment options and poor prognosis. Our research on MEITL has uncovered its genetic portrait including hallmark SEDT2 mutations, expanded its pathological spectrum, and identified molecular biomarkers influencing patients’ outcome. In this study, we aimed to establish and clarify the similar and diverging features of EATL. Methods : A large combined cohort of patients with EATL (n=30) and MEITL (n=52) was assembled and tumor samples were used for whole-exome and RNA sequencing profiling.

  Study EGAS50000001126

• Stage-specific gene and transcript dynamics in human male germ cells

  The testis is one of the most transcriptionallyactive organs, however how germ cell differentiation is controlled at the molecular level remains largely unknown. To study global transcriptional dynamics during human spermatogenesis we sequenced total RNA of human testicular biopsies with 5 specific histological phenotypes: Sertoli cell-only (SCO, n=3), spermatogenic arrests at the spermatogonial (SPG, n=4), spermatocyte (SPC, n=3), and spermatid (SPD, n=3) level, as well as normal spermatogenesis (Normal, n=3). To our knowledge, this work provides the most complete capture of the transcriptome and its dynamics during human spermatogenesis to date.

  Study EGAS00001006135

• The molecular landscape of glioma in patients with Neurofibromatosis 1.

  Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the most prominent tumor type. Gliomagenesis in NF1 results in heterogeneous spectrum of tumors, from low grade to high grade glioma, occurring during the entire patient lifespan. In this study, we present the molecular landscape of low- and high-grade glioma in children and adults affected by NF1 (NF1-glioma). 59 tumor samples from 56 NF1-glioma patients with 43 matched normal were profiled with Whole Exome Sequencing, DNA Methylation array (31 tumors) and RNA sequencing (29 tumors).

  Study EGAS00001003186

• Multiple Tissue Monitoring in Huntington disease - RNAseq skeletal muscle

  We examined whether peripheral tissues can serve as a source of readily accessible biological signatures at the RNA and protein level in Huntington disease (HD) patients. Under the MTM-HD study we generated large, high-quality human datasets from skeletal muscle, skin and adipose tissue, as well as primary human fibroblast lines to probe molecular changes in human pre-manifest and early manifest HD patients. We document the involvement of inflammation, energy metabolism and extracellular vesicle homeostasis. This demonstrates the potential to identify biological signatures from peripheral tissues in HD suitable as biomarkers in clinical trials.

  Study EGAS00001006474

• Multiple Tissue Monitoring in Huntington disease - RNAseq fibroblasts

  We examined whether peripheral tissues can serve as a source of readily accessible biological signatures at the RNA and protein level in Huntington disease (HD) patients. Under the MTM-HD study we generated large, high-quality human datasets from skeletal muscle, skin and adipose tissue, as well as primary human fibroblast lines to probe molecular changes in human pre-manifest and early manifest HD patients. We document the involvement of inflammation, energy metabolism and extracellular vesicle homeostasis. This demonstrates the potential to identify biological signatures from peripheral tissues in HD suitable as biomarkers in clinical trials.

  Study EGAS00001006472

• Multiple Tissue Monitoring in Huntington disease - RNAseq adipose tissue

  We examined whether peripheral tissues can serve as a source of readily accessible biological signatures at the RNA and protein level in Huntington disease (HD) patients. Under the MTM-HD study we generated large, high-quality human datasets from skeletal muscle, skin and adipose tissue, as well as primary human fibroblast lines to probe molecular changes in human pre-manifest and early manifest HD patients. We document the involvement of inflammation, energy metabolism and extracellular vesicle homeostasis. This demonstrates the potential to identify biological signatures from peripheral tissues in HD suitable as biomarkers in clinical trials.

  Study EGAS00001006473

• Whole blood RNA-sequencing of covid-19 patients and healthy controls

  This dataset contains whole blood transcriptome data generated from 93 patients with COVID-19 across a range of severities and 23 healthy controls. All patients were PCR positive for SARS-CoV-2 and disease severity ranged from asymptomatic to severe disease requiring ventilation. Individuals without symptoms, or with mild symptoms, were recruited from routine screening of healthcare workers, while COVID-19 patients were recruited at or soon after admission to Addenbrooke’s or Royal Papworth hospitals. Blood samples were taken at recruitment and then again four weeks later. Further details of the cohort and the generation of the RNA-Sequencing data can be obtained from Bergamaschi, L. et al. Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease. Immunity 54, 1257-1275 e8 (2021).

  Dataset EGAD00001007776

• Multiregional single cell RNA sequencing of human renal cell carcinoma

  The dataset comprises of 5' single cell RNA sequencing with TCR enrichment with 10x Genomics' Chromium technology of multiregional biopsies of human renal cell carcinomas. Biopsies from different tumour regions, the tumour-normal interface, normal kidney, normal adrenal, metastatic regions, peri-nephric fat, and peripheral blood were sequenced from 12 patients with kidney tumours.

  Dataset EGAD00001008030

• Peripheral blood DNA methylation data from CD patients prior to and during ustekinumab treatment from AmsterdamUMC

  Longitudinal DNA methylation discovery data as obtained using the Illumina HumanMethylation EPIC BeadChip array (V1) on peripheral blood from CD patients at the AmsterdamUMC prior to and during ustekinumab treatment

  Dataset EGAD00010002649

• Peripheral blood DNA methylation data from CD patients prior to ustekinumab treatment from John Radcliffe Hospital

  DNA methylation validation data as obtained using the Illumina HumanMethylation EPIC BeadChip array (V1) on peripheral blood from CD patients at the John Radcliffe Hospital, Oxford, UK prior to ustekinumab treatment

  Dataset EGAD00010002650

• Peripheral blood DNA methylation data from CD patients prior to and during vedolizumab treatment from AmsterdamUMC

  Longitudinal DNA methylation discovery data as obtained using the Illumina HumanMethylation EPIC BeadChip array (V1) on peripheral blood from CD patients at the AmsterdamUMC prior to and during vedolizumab treatment

  Dataset EGAD00010002651

• Peripheral blood DNA methylation data from CD patients prior to vedolizumab treatment from John Radcliffe Hospital

  DNA methylation validation data as obtained using the Illumina HumanMethylation EPIC BeadChip array (V1) on peripheral blood from CD patients at the John Radcliffe Hospital, Oxford, UK prior to vedolizumab treatment

  Dataset EGAD00010002652

• HeH_SNParry

  This dataset included 110 samples with high hyperdiploid acute lymphoblastic leukemia that were genotyped using Affymetrix SNP Array or Illumina's BeadArray platform.

  Dataset EGAD00010002456

• Whole Genome - HAP-1 clones

  Whole genome sequencing on HAP-1 clones wild-type or knockout for MBD4 and/or TDG. Libraries were prepared using the Kapa HyperPrep kit (Roche, 07962363001). Paired-end libraries (2 x 100 bp) were sequenced on a NovaSeq 6000 instrument (Illumina).

  Dataset EGAD50000000765

• WES patients with colorectal polyposis

  Twenty-seven patients were included and subjected to germline WES using NovaSeq 6000 platform. After filtering out variants for sequencing quality, variant allele fraction frequency, and population frequency, variants were manually prioritized by the ACMG criteria.

  Dataset EGAD50000000842

• Moroccan Genome Project: Sequencing Data from 109 Whole Genomes of Moroccan Individuals

  This study is the first phase of the Moroccan Genome Project, which included the complete sequencing of 109 genomes from the Kingdom of Morocco. The sequencing was performing using the Illumina NovaSeq6000 platform, with a mean coverage of 30X.

  Dac EGAC50000000353

• TMT_proteomics_CUD

  CUD samples: TMT-proteomics using Orbitrap FusionTM LumosTM TribridTM Mass Spectrometer, TMT10plex (N=8 sample batch) or TMT16plex (2x N=16 sample batches) Isobaric Label Reagent (Thermo Fisher Scientific, Waltham, MA, USA), experiment type: bottom-up proteomics; data-dependent acquisition.

  Dataset EGAD00010002703

• TMT_proteomics_Ctrl

  Ctrl samples: TMT-proteomics using Orbitrap FusionTM LumosTM TribridTM Mass Spectrometer, TMT10plex (N=8 sample batch) or TMT16plex (2x N=16 sample batches) Isobaric Label Reagent (Thermo Fisher Scientific, Waltham, MA, USA), experiment type: bottom-up proteomics; data-dependent acquisition.

  Dataset EGAD00010002702

• Genetic architecture of disease in Greenland is shaped by demographic history, fine-structure, and selection - WGS data

  This file set has 448 Greenlandic individuals sequenced using Illumina 150 Paired end sequencing and has an average sequencing depth of 35X. The data is unfiltered, in VCF format, and covers 19.751.308 variants.

  Dataset EGAD50000000933

• Duplex sequencing of 26 genes

  Buccal samples and paired esophageal epithelium were obtained using the three sizes of swabs and endoscopic biopsy, respectively. Forty samples from 10 subjects were analyzed via duplex sequencing. This dataset contains bam files that were mapped to the GRCh37 reference genome.

  Dataset EGAD50000000998

• Hybrid Capture of PyBKV integration in Urothelial Carcinoma from Kidney Transplant

  Hybrid Capture of PyBKV integration in Urothelial Carcinoma from Kidney Transplant. The Panel was designed using Agilent SureDesign on SureSelect XTHS Hybrid Capture Panel. Sequencing was done on Illumina NovaSeq 6000

  Dataset EGAD50000001548

• DNA methylation and transposable element landscapes in human regulatory and conventional Tcells

  Whole genome bisulfate sequencing using tagmentation of Tcells from skin and blood.The method improved TWGBS protocol (Weichenhan et al.), Methods Mol. Biol. 2018, vol. 1708 pp.105-122) was used

  Dataset EGAD50000001022

• SIA Subtyping Shallow Whole Genome Sequencing (sWGS)

  Associated with Molecular classification of small intestinal adenocarcinomas. Shallow Whole Genome Sequencing (sWGS) generated 214 .fastq files from 127 small intestine adenocarcinomas from 125 patients. DNA libraries for shallow whole genome sequencing were prepared using TruSeq Nano kits (Illumina).

  Dataset EGAD50000001760

• Phenytoin_case-control

  Genotype dataset from individuals diagnosed with phenytoin-induced Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) and control individuals from the Thai population. DNA was extracted from whole blood, and SNP genotyping was performed using the Illumina HumanOmniExpressExome-8 v1.2 array.

  Dataset EGAD00010002790

• Single-cell multidimensional profiling of tumor cell heterogeneity in supratentorial ependymomas

  55 Supratentorial Ependymomas patient samples were sequenced scRNA-sequencing using Smart-Seq2 and 10x protocol (51 samples) and 10x Genomics protocol (4 samples) on a NextSeq 550 sequencer (Illumina).

  Dataset EGAD50000002186

• EPC (eccrine porocarcinoma) WES samples

  Whole-exome sequencing (WES) in a well-characterized sample of 14 matched EP tumour/healthy surrounding tissue samples. The sequencing was done with paired EXOME sequencing on Illumina HiSeq 4000 using Agilent SureSelect XT HS + Human All Exon V7.

  Dataset EGAD00001006395

• ICGC PCAWG Dataset: PAEN-AU_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: PAEN-AU.

  Dataset EGAD00001002154

• 16S data from IBD patients

  Bacterial 16S V4 rDNA was amplified using two differently barcoded V4 fusion primers. Pooled PCR samples were purified and paired-end sequenced on MiSeq instrument for 250 cycles. The steps from DNA quantification to sequencing were conducted at Second Genome Inc.

  Dataset EGAD00001005482

• ICGC PCAWG Dataset: LICA-FR_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: LICA-FR.

  Dataset EGAD00001002016

• Mutation analysis AVENIO of NSCLC patients

  Mutation analysis of 77 frequently mutated genes in NSCLC in plasma DNA and corresponding PBMCs of NSCLC patients under ICI using the AVENIO Expanded Kit.

  Dataset EGAD00001007930

• ICGC PCAWG Dataset: PACA-CA_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: PACA-CA.

  Dataset EGAD00001003162

• ICGC PCAWG Dataset: BOCA-UK_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: BOCA-UK.

  Dataset EGAD00001002125

• ICGC PCAWG Dataset: MALY-DE_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: MALY-DE.

  Dataset EGAD00001002123

• Martin_Ravenscroft-AUS1

  Whole genome sequencing data on D19-0702 (AUS1), presented in Martin et al. 2020 (AUS1). WGS (Illumina HiSeq) was performed at Kinghorn Centre for Clinical Genetics, Garvan Institute of Medical Research. Data was analyzed using the Seave bioinformatic analysis pipeline (https://www.seave.bio).

  Dataset EGAD00001006276

• ICGC PCAWG Dataset: CLLE-ES_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: CLLE-ES.

  Dataset EGAD00001002130

• ICGC PCAWG Dataset: RECA-EU_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: RECA-EU.

  Dataset EGAD00001002131

• ICGC PCAWG Dataset: PBCA-DE_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: PBCA-DE.

  Dataset EGAD00001002127

• ICGC PCAWG Dataset: EOPC-DE_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: EOPC-DE.

  Dataset EGAD00001002124

• ICGC PCAWG Dataset: LINC-JP_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: LINC-JP.

  Dataset EGAD00001002662

• ICGC PCAWG Dataset: BRCA-EU_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: BRCA-EU.

  Dataset EGAD00001002129

• ICGC PCAWG Dataset: PRAD-UK_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: PRAD-UK.

  Dataset EGAD00001002126

• ICGC PCAWG Dataset: PRAD-CA_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: PRAD-CA.

  Dataset EGAD00001002128

• ICGC PCAWG Dataset: PACA-AU_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: PACA-AU.

  Dataset EGAD00001002132

• ESGI - Whole Genome Sequencing of samples from the Cilentogen isolates (2019-08-19)

  Deep whole genome sequencing of sampels from the Cilento isolates. The samples are sequenced using the Illumina HiSeq X Ten system. . This dataset contains all the data available for this study on 2019-08-19.

  Dataset EGAD00001005266

• ICGC PCAWG Dataset: ESAD-UK_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: ESAD-UK.

  Dataset EGAD00001002156

• ICGC PCAWG Dataset: LIRI-JP_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: LIRI-JP.

  Dataset EGAD00001002155

• ICGC PCAWG Dataset: MELA-AU_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: MELA-AU.

  Dataset EGAD00001002157

• Human_Evolution_3B

  The mtDNA and Y chromosome of up to 15 Australian Aborigines, concentrating on individuals with indigenous lineages will be sequenced using the standard whole-genome sequencing followed by filtering out autosomal and X sequences, so that only mtDNA and the Y chromosome would be analysed and released.

  Dataset EGAD00001001374

• ICGC PCAWG Dataset: GACA-CN_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: GACA-CN.

  Dataset EGAD00001003132

• ICGC PCAWG Dataset: OV-AU_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: OV-AU.

  Dataset EGAD00001003227

• Whole Exome Data of RFWD3 Fanconi anemia patient

  Dataset contains one sample derived from gDNA of human fibroblasts. Files are in FASTQ format and were generated using the Agilent SureSelect Human All Exon 50Mb Kit and followed by Next Generation Sequencing on a HighSeq2000 instrument (Illumina).

  Dataset EGAD00001003311

• WGS data of XPC-ko human small intestinal organoid cultures

  Whole genome sequencing (WGS) data of human small intestinal organoid cultures, which were deleted for the XPC gene using CRISPR-Cas9. Contains WGS data of 1 clone and 1 subclone.

  Dataset EGAD00001003779

• SLC9A3R1 variant associated with age-related hearing loss

  The dataset contains one BAM file that includes a SLC9A3R1 variant identified in two Italian patients affected by age-related hearing loss. Data have been produced by targeted re-sequencing, using Ion Torrent PGM platform.

  Dataset EGAD00001004171

• LBC1921 fastq files

  297 members of the LBC1921 were sequenced using the Illumina HiSeq X platform. This dataset contains the fastq files.

  Dataset EGAD00001008775

• Characterization of Arabian Peninsula whole exomes

  We conducted whole exome sequencing (using the SureSelect Human All Exon V5 + UTRs target enrichment kit) of 90 individuals from AP (23 from Saudi Arabia, 24 from Yemen, 24 from Oman and 19 from UAE).

  Dataset EGAD00001009162

• Paired diagnostic and relapse medulloblastoma sequencing

  Paired diagnostic and relapse medulloblastoma sequencing. Targetted panel sequencing (n=8 relapse, n=7 matched diagnostic). Whole exome sequencing (n=23 relapse, n=18 matched diagnostic). Capture using Agilent SureSelect.

  Dataset EGAD00001010321

• Profiling Chromatin Accessibility in Humans Using Adenine Methylation and Long-Read Sequencing

  This dataset includes raw nanopore, base-called, and 6mA frequency data for EcoGII-treated NA12878 and MCF7 chromatin samples. It also includes raw nanopore data for the HG002 EcoGII-treated DNA.

  Dataset EGAD00001015374

• MASS_Pilot: Muscle and Ageing Science Study - Collaboration with Wellcome Sanger Institute to characterise skeletal muscle ageing using Human Cell Atlas approaches (2025-07-31)

  Transcriptomic analysis of skeletal muscle, to understand the mechanisms of muscle ageing. . This dataset contains all the data available for this study on 2025-07-31.

  Dataset EGAD00001015670

• ICGC PCAWG Dataset: LAML-KR_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: LAML-KR.

  Dataset EGAD00001002119

• ICGC PCAWG Dataset: ORCA-IN_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: ORCA-IN.

  Dataset EGAD00001002120

• ICGC PCAWG Dataset: BTCA-SG_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: BTCA-SG.

  Dataset EGAD00001002121

• ICGC PCAWG Dataset: BRCA-UK_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: BRCA-UK.

  Dataset EGAD00001002122

• ICGC PCAWG Dataset: PAEN-IT_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: PAEN-IT.

  Dataset EGAD00001002153

• ICGC PCAWG Dataset: CMDI-UK_PCAWG_WGS_BWA

  ICGC PCAWG Dataset for WGS BAM aligned using BWA MEM. Project: CMDI-UK.

  Dataset EGAD00001002664

• H3Africa TrypanoGEN Main WGS

  This dataset is for TrypanoGEN Phase 1: Variant discovery, and includes 233 samples sequenced to approximately 10X coverage. Samples are from Guinea, Cote D’Ivoire, DRC and Uganda using Illumina HiSeq 2500.

  Dataset EGAD00001005076

• Method to Assess Lung Water Accumulation During Exercise

  The goal of this non-significant risk medical device study is to test the initial technical feasibility of a 0.55T MRI in healthy volunteers by technical optimization of scanner protocols, and to test accuracy of standard MR measurements in adult patients with known stable disease. Exercise-induced lung water is a key feature in heart failure. Dynamic quantitative lung water imaging during exercise stress is therefore of interest to unmask latent heart failure. We developed a novel magnetic resonance imaging (MRI) method using a proton density weighted ultrashort echo time MRI sequence along with a time-resolved and respiratory motion compensated image reconstruction for exercise lung water imaging. We validated our method in a porcine model of dynamic lung water accumulation (n=5), and tested its feasibility for use in humans using 12 healthy subjects, 1 patient with heart failure with preserved ejection fraction, and 1 patient with heart failure with reduced ejection fraction. Data suggest the novel imaging method is capable of dynamically imaging lung water accumulation during exercise stress. Reference 1 (PMID: 37288601) contains the main results for this study.

  Study phs003346

• Nicotine dependence GWAS meta-analysis across European and African American ancestries

  Cigarette smoking is the leading cause of preventable morbidity and mortality. Knowledge is evolving on genetics underlying initiation, regular smoking, nicotine dependence (ND), and cessation. We performed a genome-wide association study using the Fagerström Test for ND (FTND) in 58,000 smokers of European or African ancestry. Five genome-wide significant loci, including two novel loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416) were identified, and loci reported for other smoking traits were extended to ND. Using the heaviness of smoking index (HSI) in the UK Biobank (N=33,791), rs2714700 was consistently associated, but rs1862416 was not associated, likely reflecting ND features not captured by the HSI. Both variants were cis-eQTLs (rs2714700 for MAGI2-AS3 in hippocampus, rs1862416 for TENM2 in lung), and expression of genes spanning ND-associated variants was enriched in cerebellum. SNP-based heritability of ND was 8.6%, and ND was genetically correlated with 13 other smoking traits (rg=0.40-0.95) and co-morbid diseases. Our results emphasize the FTND as a composite phenotype that expands genetic knowledge of smoking, including loci specific to ND.

  Study phs001532

• Whole Exome Sequencing in Alopecia Areata Identifies Rare Mutations in KRT82

  Alopecia areata (AA) is an autoimmune disorder, in which the body's own immune cells attack hair follicels resulting in hair loss. It is a complex genetic disease with 14 associated loci previously identified in our genome-wide association study (GWAS). In the study, we performed the whole-exome sequencing (WES) on 849 AA patients with the aim to identify the novel rare variants in genes contributing to AA susceptibility. We performed gene-collapsing analyses and identified keratin 82 (KRT82 Gene ID: 3888) as the highest associated AA gene in the three rare damaging collapsing models with p<6.7E-07 in one of the models. The KRT82 gene is a hair-specific type II keratin expressed in the hair shaft cuticle during the anagen phase of the hair cycle. We reported the lower expression of KRT82 in AA hair follicles, compared to controls, and the KRT82 expression is absent from the bulb region, the site of AA immune attack. This study emphasizes the significance of using WES and gene collapsing analyses to identify rare variation in a functionally relevant risk gene using a moderate sample size.  

  Study phs002632

• Genomic Data Archive From the Network for Pancreatic Organ Donors With Diabetes

  The Network for Pancreatic Organ Donors with Diabetes (nPOD) is the largest biorepository of human pancreata from organ donors with type 1 diabetes (T1D), maturity-onset diabetes of the young (MODY), cystic fibrosis-related diabetes (CFRD), type 2 diabetes (T2D), gestational diabetes, and islet autoantibody positive (AAb+)/pre-T1D. The mission of the nPOD is to distribute biospecimens and associated de-identified data/metadata to an international researcher network, and to promote the development of new treatments for these diabetes conditions. Here, we describe the release of high-parameter genotyping data for the nPOD cohort. Specifically, 372 subjects were genotyped using a customized precision medicine single nucleotide polymorphism (SNP) microarray (UFDIchip). These data were technically validated using published algorithms to evaluate donor relatedness, ancestry, imputed HLA, and T1D genetic risk score. Additionally, 207 subjects were queried for rare known and novel coding region variants via whole exome sequencing (WES). These data are now publicly available, enabling genotype-selected sample requests and the study of novel genotype : phenotype associations, ultimately to explain diabetes heterogeneity and inform precision medicine strategies to interrupt diabetes pathogenesis.

  Study phs002861

• Blood Group Genotypes and Phenotypes in Omani Blood Donors and Its Links With Susceptibility to Malaria

  The Omani population experienced endemic malaria prior to eradication in the late 1990's. Since malaria is known to be a strong selective pressure on the human genome, particularly at blood group associated loci, we aimed to understand how selective pressures from malaria may be affecting genetic variation at blood group loci. Blood samples were collected from 100 healthy, Omani blood donors. Serology testing for 10 clinically relevant blood groups and whole genome sequencing (WGS) to an average coverage of 16X were performed on all samples. Additionally, using the WGS data, genetic variants (SNPs and INDELs) were called for chromosomes 1 - 22 using GRCh38. We find signals of selection at the Plasmodium vivax associated locus, ACKR1 (the Duffy blood group), but not at any Plasmodium falciparum associated loci. We also characterized several previously undescribed blood group alleles in the Omani population affecting antigenic expression, mostly at the RHD, RHCE, and GYPB loci. The data available from this project include BAM files from 100 Omani samples aligned to GRCh38, per chromosome VCF files, and results from the serology tests for all 10 blood groups.

  Study phs003694

• Development of a diagnostic gene panel for Gorlin syndrome and its application to liquid biopsy

  Gorlin syndrome is an autosomal dominant, rare disease caused by mutations in PTCH1, PTCH2, and SUFU with various symptoms in multiple organs making early diagnosis challenging. In this study, we generated a Gorlin syndrome gene panel that could help to overcome the difficulties in diagnosing Gorlin syndrome using a single test. This gene panel is time- and cost-efficient and highly reliable with a high-quality score of 30, on-target ratio, and coverage depth, and could detect more mutations than whole-exome sequencing of the same patient. Although the current in silico prediction tools have a limited genetic database of gene mutations in rare hereditary diseases, five prediction tools were used to identify pathological mutations. Pathogenic gene mutations were detected not only in PTCH1 but also in PTCH2 in five out of 12 patients with Gorlin syndrome diagnosed based on clinical symptoms. Using this gene panel, we showed the same gene mutation in the patients and their asymptomatic relatives; hence, it has enabled a highly reliable genetic diagnosis of Gorlin syndrome at a low cost requiring only blood sample.

  Study JGAS000308

• Determination_of_cell_specific_regulatory_enhancers_in_hematopoetic_models

  The BLUEPRINT project is a large-scale project investigating epigenetic mechanisms involved in blood formation, in health and disease. The human variation workpackage (WP10) of the project seeks to characterize the effect of common sequence variation on the epigenome status of a cell. To do this, the project will use highly purified blood cells to minimise “experimental noise” and therefore enhance the power to discover modest effects. Two peripheral blood cell types, the CD14+CD16- monocyte (an important central orchestrator of adaptive immunity and a bridge between innate and adaptive immunity) and the CD65+CD9- neutrophilic granulocyte (the frontline cell for innate immunity) have been selected for this purpose. The two types of cells will be obtained at high purity from adult blood (AB) of 200 healthy males and females, respectively. Cells will be purified by using already validated and fully operational protocols that are based on density gradient centrifugation of the buffy coat obtained from whole blood, followed by magnetic bead-based purification using monoclonal antibodies against Cluster of Differentiation (CD) lineage-specific cell surface markers. This data set contains functional genomics data for gene expression and chromatin state.

  Study EGAS00001000586

• Duplexseq_of_the_interstrand_crosslinks_WGS

  One of the most dangerous forms of DNA damage are interstrand crosslinks (ICLs), which covalently crosslink the two strands of the DNA double helix. The repair of these lesions is crucial for cellular survival due to their ability to block transcription and DNA replication. Initially, the major pathway that has been described in ICL repair involves a network of 22 genes that are mutated in a severe human genetic disease known as Fanconi Anemia (FA). Using synthetic lethality screens in the near-haploid human HAP1 cell line, we recently identified two potentially novel regulators of ICL repair, C1orf112 and THAP12. Loss of C1orf112 and THAP12 causes hypersensitivity to ICL-inducing DNA damaging agents, such as Mitomycin C (MMC). Additionally, C1orf112-depleted cells show elevated levels of micronuclei and accumulation of DNA damage in S-phase. To better understand how C1orf112 and THAP12 mediate the repair of ICLs, we want to perform mutational signature analysis, using the BotSeq method. Therefore, WT, C1orf112 and THAP12 knockout cells were cultured in vehicle or MMC treated conditions for 10 days and the genomic DNA was isolated. FANCA and FANCD2 knockout cells are taken along as controls in this experimental setting.

  Study EGAS00001006545

• Genomic_Advances_in_Sepsis__GAinS__genotyping

  This cohort comprises a subset of pateints enrolled in the Genomic Advances in Sepsis (GAinS) study, an established biobank of adult sepsis patients. Patients with sepsis due to community acquired pneumonia or faecal peritonitis were recruited from 35 hospitals across the UK from 2005-2018, with samples for functional genomics and detailed clinical information collected over the first five days of ICU admission. DNA was extracted from buffy coat or whole blood samples using the Qiagen DNA extraction protocol, the automated Maxwell Blood purification kit (Promega), or the QIAamp Blood Midi kit protocol (Qiagen). Genotyping data were generated using the Illumina HumanOmniExpress BeadChip (295 patients), the Infinium CoreExome BeadChip (655 patients), and the Infinium Global Screening Array BeadChip (307 patients). Genotyping QC and imputation into the Haplotype Reference Consortium was perfomed within each batch. The datasets were combined and following post-imputation filtering data were available on 1168 samples. 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/

  Study EGAS00001007786

• Reference Exome Data for a Northern Brazilian population

  Whole exome sequencing (WES) is a popular technology widely used in the diagnosis of rare genetic diseases and provides useful variant data for analysis of complex diseases. However, there is not always adequate population-specific reference data available to assist clinical geneticists in assigning a diagnostic variant to a specific clinical condition. Here we provide a catalogue of variants called after sequencing the exomes of 45 babies from the State of Rio Grande do Nord in Brazil. Sequence data were processed using an ‘intersect-then-combine’ (ITC) approach, using GATK and SAMtools to call variants. A total of 612,761 variants were identified in at least one individual in this Brazilian Cohort, including 559,448 single nucleotide variants (SNVs) and 53,313 insertion/deletions. Of these, 58,111 overlapped with nonsynonymous (nsSNVs) or splice site (ssSNVs) SNVs in dbNSFP. As an aid to clinical diagnosis of rare diseases, we used the American College of Medicine Genetics and Genomics (ACMG) guidelines to assign pathogenic/likely pathogenic status to 439 (0.755%) of the 58,111 nsSNVs and ssSNVs. Our data set provides a useful reference point for diagnosis of rare diseases in Brazil.

  Study EGAS00001004112

• H3Africa - An integrated approach to the identification of genetic determinants of susceptibility to trypanosomiasis

  The objective of the TrypanoGEN project is to discover genetic variants associated with different responses to sleeping sickness infection. The project was designed in two phases:Phase 1) Variant discovery; 222 samples were sequenced to approximately 10X coverage on an Illumina 2500 with 2x150bp reads, at the University of Liverpool Center for Genomic Research. In addition, 77 samples from Cameroon and Zambia were sequenced to approximately 30X Coverage at Baylor College of Medicine. The sequenced reads were mapped onto the 1000 genomes project human_g1k_v37_decoy reference genome using BWA. The SNP calling on all the samples was done using the genome analysis tool kit GATK v3.4. Samples were selected from seven populations where Trypanosomiasis is endemic: Nilo-Saharan speakers from North-West Uganda and Niger-Congo speakers from South-East Uganda, DRC, Ivory Coast, Guinea, Cameroon and Zambia. The samples included 182 controls, 97 cases, 17 latent infections and 3 suspect cases. Phase 2) Variants discovered in Phase 1 will be used in the development of the H3Africa SNP chip. This chip will then be used in a GWAS study to identify variants associated with trypanosomiasis.

  Study EGAS00001002602

• Clonal Decomposition and DNA Replication States Defined by Scaled Single-Cell Genome Sequencing

  Accurate measurement of clonal genotypes, mutational processes, and replication states from individual tumor-cell genomes will facilitate improved understanding of tumor evolution. We have developed DLP+, a scalable single-cell whole-genome sequencing platform implemented using commodity instruments, image-based object recognition, and open source computational methods. Using DLP+, we have generated a resource of 51,926 single-cell genomes and matched cell images from diverse cell types including cell lines, xenografts, and diagnostic samples with limited material. From this resource we have defined variation in mitotic mis-segregation rates across tissue types and genotypes. Analysis of matched genomic and image measurements revealed correlations between cellular morphology and genome ploidy states. Aggregation of cells sharing copy number profiles allowed for calculation of single-nucleotide resolution clonal genotypes and inference of clonal phylogenies and avoided the limitations of bulk deconvolution. Finally, joint analysis over the above features defined clone-specific chromosomal aneuploidy in polyclonal populations.

  Study EGAS00001003190

• Comprehensive spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer

  Although immunosuppressive and pro-metastatic functions of FAP+ Cancer-Associated Fibroblasts (CAF) are well-established, their plasticity and spatial distribution remain poorly understood. Here, we analyze trajectory inference, deconvolute spatial transcriptomics at single-cell level and perform functional assays to generate an integrative high-resolution map of breast cancer (BC), focusing particularly on the different subpopulations within inflammatory and myofibroblastic (iCAF/myCAF) FAP+ CAF. We identify 10 spatially-organized FAP+ CAF-related cellular niches, called EcoCellTypes, which are precisely localized within tumors. Consistent with their spatial organization, we identify DPP4- and YAP1-dependent mechanisms, by which cancer cells drive the transition of the detoxification-associated inflammatory FAP+ CAF cluster (Detox-iCAF) towards immunosuppressive extracellular matrix (ECM)-producing myofibroblasts (ECM-myCAF). In turn, ECM-myCAF polarize TREM2+ macrophages and regulatory NK cells to induce immunosuppressive EcoCellTypes. FAP+ CAF subpopulations accumulate differently depending on the invasive BC status and predict invasive recurrence of ductal carcinoma in situ (DCIS), which could help in identifying low-risk DCIS patients eligible for therapeutic de-escalation.

  Study EGAS50000000220

• Impact of germline pathogenic variants in 27 cancer-predisposing genes on the risk of lymphoma

  The application of advanced molecular technology has significantly expanded lymphoma classification, allowing risk stratification and treatment optimization. Limited evidence suggests the presence of a genetic predisposition in lymphoma, indicating the potential for better individualized clinical management based on a novel lymphoma classification. Herein, we examined the impact of germline pathogenic variants in 27 cancer-predisposing genes with lymphoma risk and explored the clinical characteristics of pathogenic variant carriers. This study included 2,066 lymphoma patients and 38,153 cancer-free controls from the Japanese population. Following quality control of sequencing data, samples from 1,982 lymphoma patients and 37,592 controls were further analyzed. Sequencing data of controls were obtained from JGAD000721. Germline pathogenic variants in some cancer-predisposing genes were associated with a high risk of lymphoma. Furthermore, germline pathogenic variants in these genes were especially associated with the higher risk of a certain subtype. These results would provide novel insights concerning monogenic form into lymphoma classification. Some lymphoma patients may benefit from surveillance and targeted treatment like other neoplasms.

  Study JGAS000347

• Dynamics of Tumor Heterogeneity from Primary to Metastatic Dissemination in Prostate Cancer

  PRO-SPeCT: PROstate cancer heterogeneity deconvolution through Single cell Profiling of Chromatin accessibility and Transcriptomic output Identifying drivers of cancer progression to guide treatment selection is hindered by limited abilities to understand tumor heterogeneity’s impact on evolution. Here, we delineated the phenotypic variability across ~300,000 prostate tumor cells collected from multiple loci in primary and matched locoregional metastases. We found inter-patient heterogeneity to be confined to malignant populations. While malignant cell populations exhibit intra-locus heterogeneity, they maintain inter-loci phenotypic similarity within a patient’s prostate gland. In addition, the intra-locus heterogeneity between malignant cell populations is paired with a common clonal architecture. Lastly, we show that malignant cell populations disseminating to locoregional lymph nodes mirror the clonal architecture and phenotypic heterogeneity observed across primary tumor loci while showcasing cell state transition toward inflammatory phenotypes. These findings provide insights into distinct measures of tumor heterogeneity, revealing diverse evolutionary paths across patients converging to common phenotypic adaptations in early prostate cancer progression.

  Study EGAS50000000524

• Circulating Tumor DNA Analysis Detects Minimal Residual Disease and Predicts Recurrence in Patients with Stage II Colon Cancer

  Detection of circulating tumor DNA (ctDNA) after resection of stage II colon cancer may identify those at the highest risk of recurrence and help inform adjuvant treatment decisions. We used massively-parallel-sequencing–based assays to evaluate the ability of ctDNA to detect minimal residual disease in 1046 plasma samples from a prospective cohort of 230 patients with resected stage II colon cancer. In patients not treated with adjuvant chemotherapy, ctDNA was detected post-operatively in 14 of 178 (7.9%) patients, 11 (79%) of whom had recurred at a median follow-up of 27 months; recurrence occurred in only 16 (9.8 %) of the 164 patients with negative ctDNA (HR, 18; 95% confidence interval [CI], 7.9 to 36; P<0.001). In patients treated with chemotherapy, the presence of ctDNA following completion of chemotherapy was also associated with an inferior recurrence-free survival (HR, 11; 95% CI, 1.8 to 68; P=0.001). ctDNA detection after stage II colon cancer resection provides direct evidence of residual disease and identifies patients at very high risk of recurrence.

  Study EGAS00001001839

• Somatic pathogenic variants in the normal mammary gland of sporadic breast cancer patients.

  The mammary gland undergoes hormonally stimulated cycles of proliferation, lactation and involution. We hypothesized that these factors increase the mutational burden in glandular tissue and may explain high cancer incidence rate in the general population and recurrent disease. Hence, we investigated the DNA sequence variants in the normal mammary gland, tumor and peripheral blood from 52 reportedly sporadic breast cancer patients, including breast-conserving surgery cases. Targeted resequencing of 542 cancer associated genes revealed mosaic somatic pathogenic variants of: PIK3CA, TP53, AKT1, MAP3K1, CDH1, RB1, NCOR1, MED12, CBFB, TBX3 and TSHR in the normal mammary gland, at considerable allelic frequencies (9x10-2 to 5.2x10-1) indicating clonal expansion. Further evaluation of the frequently damaged PIK3CA and TP53 genes by ultra-sensitive duplex sequencing demonstrated a diversified picture of multiple low level-mosaic (in 10-2 to 10-4 alleles) hotspot pathogenic variants. Our results raise a question about the oncogenic potential in non-tumor mammary gland tissue of breast-conserving surgery patients.

  Study EGAS00001005698

• A combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancer

  The earlier diagnosis of cancer is one of the keys to reducing future cancer deaths. Here we describe our efforts to develop a non-invasive, blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinoma and 185 control patients without known cancers. KRAS mutations were detected in the plasma of 66 patients (30%) and every mutation found in the plasma was identical to that subsequently found in the patients' primary tumor (100% concordance). The use of KRAS in conjunction with two thresholded protein biomarkers (CA19-9 and prolactin) increased the sensitivity to 67%. Only one of the 185 plasma samples from the control cohort were positive for any of the three markers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types.

  Study EGAS00001002444

• Genetic and epigenetic variation at regulatory regions contribute to cancer evolution under endocrine treatment

  Comprehensive profiling of hormone-dependent breast cancer (HDBC) has identified hundreds of protein-coding alterations contributing to cancer initiation, but only a handful have been linked to endocrine therapy resistance, potentially contributing to 40% of relapses. If other mechanisms underlie the evolution of HDBC under adjuvant therapy is currently unknown. In this work, we employ integrative functional genomics to dissect the contribution of cis-regulatory elements (CREs) to cancer evolution by focusing on 12 megabases of non-coding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Massive parallel perturbation in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance9. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies non-coding changes involved in therapy resistance. Overall, our data uncover actionable transient transcriptional programs critical for dormant persister cells and unveil new regulatory nodes driving evolutionary trajectories towards disease progression.

  Study EGAS00001006340

• Genetics of Neuropsychiatric and Neurodevelopmental Disorders

  Although schizophrenia is a highly heritable disease, relatively little progress had been made in securely identifying the genetic causes of this disorder, and most instances of schizophrenia in the general population remain unexplained. One avenue of explanation for the genetic basis of schizophrenia, however, has been effectively closed by recent research. Genome-wide association studies (GWAS) have now shown that common variation makes at most a modest contribution to the risk of schizophrenia. At the same time that the role of common variation has been circumscribed by GWAS, however, the analysis of copy number variants that are detectable on a genome-wide scale has revealed and replicated a number of very rare variants that associate with schizophrenia. These rare copy number variants that have been implicated in schizophrenia, however, have one striking feature in common: they are all risk factors for other brain related disorders beyond schizophrenia such as mental retardation, autism and epilepsy. These findings argue that genetic risk factors may confer a highly penetrant vulnerability to neuropsychiatric disorder, which is then further modified by interacting genetic or environmental factors to determine the ultimate manifestation. Most schizophrenia collections that are being studied today, however, have been selected precisely for their homogeneity: including only schizophrenia patients with no comorbidities, or schizophrenia patients with relatives who have schizophrenia but no other neuropsychiatric conditions. These selection criteria are inconsistent with what we now know about the bulk of the genetic differences that have been associated with disease. The central hypothesis of this project is that there are rare genetic variants that strongly elevate the risk of various neuropsychiatric diseases, and that these risk factors can be identified most readily in families segregating multiple neuropsychiatric conditions.

  Study phs000682

• Gabriella Miller Kids First Pediatric Research Project in Microtia in Hispanic Populations

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). All of the WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Microtia is a rare congenital deformity of the external ear, the pinna. The severity of microtia is variable and ranges from subtle deformities in the pinna to absence of the external ear. Microtia is often associated with closure of the external auditory ear canal causing significant hearing loss. Microtia can be an isolated, unilateral or bilateral malformation, or occur solely with ear canal deformities, or with additional craniofacial or syndromic manifestations. Earlier studies of identical twins with microtia demonstrated a significant genetic contribution. The molecular pathogenesis for most microtia remains unknown. We propose to leverage our clinical acumen in diagnosis and treatment of microtia (R.E.), our relationship to the microtia community (M.T.) and our collected DNA samples from microtia patients to identify genetic variant(s) that contribute to this congenital malformation. Microtia prevalence is much higher among Native Americans and some Latin Americans (17 per 10000 Ecuadorian births) than among individuals of European-descent (0.6 -1.6 per 10,000 births). To capitalize on this epidemiologic data, we have recruited microtia cohorts from Latin America and the U.S, including clinical data and DNA samples.

  Study phs002172

• Genomic Evolution of Low- and High-Grade Glioma

  Malignant transformation (MT) of IDH-mutant low-grade glioma (LGG) to aggressive high-grade tumors is an event of major clinical significance, eventually leading to death in the majority of LGG patients. While patients with primary glioblastoma (GBM) have benefited from increased overall survival due to treatment with the alkylating chemotherapy temozolomide (TMZ), the benefit of TMZ for patients with diffuse low-grade gliomas (LGG) remains unknown. To further explore the relationships among TMZ treatment, hypermutation and malignant progression, we studied tumor evolution in an expanded cohort of untreated and TMZ-treated patients by exome-sequencing of paired IDH1/2-mutant LGGs and their post-TMZ recurrences. Together, these findings further our understanding of the molecular features and clinical behavior of hypermutated clones. The heterogeneity present in individual tumors, i.e. intratumoral heterogeneity (ITH), is thought to be a major reason why targeted treatments eventually fail. However, we know little about ITH in most human tumors because studies typically analyze one biopsy per tumor without knowledge of where in the tumor the sample was taken. Understanding how malignant and non-malignant cellular populations are distributed in 3D tumor space is foundational knowledge for resolving how human tumors grow, with translational implications for identifying representative biopsy specimens and predicting the impact of targeted therapy. Diffuse gliomas are incurable brain tumors with variably aggressive molecular subtypes. To determine the extent of ITH and its 3D organization in diffuse glioma, we prospectively collected a median of 10 spatially mapped samples from newly diagnosed and recurrent patient tumors, including aggressive canonical IDH1/IDH2 wild-type (IDH-wtc) glioblastoma, slower-growing IDH1/IDH2 mutant (IDHmut) glioma and a noncanonical IDH-wt glioblastoma (IDH-wtnc) lacking the TERT promoter mutation typical of canonical Glioblastoma.

  Study phs002034

• Study of Osteoporotic Fractures (SOF)

  The Study of Osteoporotic Fractures (SOF) is a prospective multicenter study of risk factors for vertebral and non vertebral fractures. The cohort is comprised of 9704 community-dwelling women 65 years old or older recruited from populations-based listings in four U.S. areas: Baltimore, Maryland; Minneapolis, Minnesota; Portland, Oregon; and the Monongahela Valley, Pennsylvania. Women enrolled in the study were 99% Caucasian with African American women initially excluded from the study due to their low incidence of hip fractures. (A cohort of AA women was recruited at the 6th Visit.) The SOF participants were followed up every four months by postcard or telephone to ascertain the occurrence of falls, fractures and changes in address. To date, follow-up rates have exceeded 95% for vital status and fractures. All fractures are validated by x-ray reports or in the case of most hip fractures, a review of pre-operative radiographs. Blood samples were collected in 6795 women at their Year 2 exam (Visit 2) and with written consent for use of DNA in genetic studies. Of these, we have GWAS data on 3625 Caucasian participants. As a separate study, the SOF Osteoarthritis Project was funded separately to collect data about risk factors for osteoarthritis (OA) and analyze baseline hip and hand films for the presence and severity of OA. Raw GWAS data is housed at the study's coordinating center and not released as part of the dbGaP release. The raw data can be requested from the study's coordinating center. Only QC cleaned PLINK files are available at dbGaP. Auxiliary files are also available for duplicates and HapMap participants.

  Study phs000510

• Genetic Progression of Head and Neck Squamous Cell Carcinoma

  These data are tumor/normal-matched exome sequencing results on 45 participants (median age of 58.6 years) treated for squamous cell carcinoma of the oropharynx at Mass Eye and Ear (MEE; Boston, MA, USA). Some tumors had two portions sequenced separately. All research complied with all relevant ethical regulations. Human subject research on patients at MEE was approved by the MEE Human Studies Committee under protocol HSC 11-024H, with informed consent obtained from participants. Participants were not compensated. Clinical data, including HPV status, were abstracted from patient records. Sequencing and clinical data were combined with TCGA data on 486 cases of head and neck squamous cell carcinoma (HNSCC). The PhylogicNDT suite of genomic analysis tools was used to infer the relative timing of genetic events during tumor progression for major molecularly defined classes of HNSCC: HNSCC negative for human papillomavirus (HPV), HPV-associated HNSCC, and HPV-negative HNSCC involving mutations in CASP8, NSD1, and NOTCH1. The timing of the development of whole-genome somatic events leading to tetraploidy or triploidy and to increased measures of intratumor genetic heterogeneity was determined. Associations of heterogeneity measures with clinical outcomes were assessed. The analysis identified genes with early mutations that likely play roles in HPV-tumor initiation (FBXW7, NOTCH1, CASP8, FAT1, NSD1, HRAS, EP300, CREBBP, KMT2D). Genes with mutations at later median relative timing (PK3CA, NFE2L2, HLA-A, SPEN, and KMT2C) were more likely to be important for progressing to later stages of the disease. Gain of chromosome arm 3q and loss of arm 11q were found to occur more frequent in HPV+ HNSCC cases. A high prevalence of 3p and 17p loss were also observed in HPV+ HNSCC cases.

  Study phs003139

• Mitochondrial DNA deletion detection in POLG patients

  Accumulation of deletions in the mitochondrial genome is a pathological hallmark of both aging and a broad range of neurometabolic disorders. Prior mtDNA deletion studies have been limited by reliance upon either long range PCR or NGS strategies that target specific regions of the mitochondrial genome. We developed an ultrasensitive high throughput sequencing process (LostArc) to identify and quantify all deletions in circular DNA molecules while minimizing interference from linear DNA and PCR artefacts. We applied this process to skeletal muscle biopsies from 19 unaffected individuals (aged 17 to 93 years) and from 22 patients with heritable mitochondrial disease (17 to 80 years) bearing pathogenic variants in POLG, the nuclear gene encoding the catalytic subunit of the mitochondrial replicative DNA polymerase ɣ (Pol ɣ). To our astonishment, LostArc revealed 35 million mtDNA deletions with ~470,000 unique deletion spans. This unprecedented volume of data enabled detailed and highly informative bioinformatics analyses. We show that ablation of mtDNA is sufficient to explain skeletal muscle phenotypes associated with aging and POLG-derived disease, with a clear threshold separating symptomatic and asymptomatic individuals. Unsupervised hierarchical clustering and principle component analysis reveal distinct age- and disease-correlated deletion patterns that implicate DNA replication by Pol ɣ in the formation of mtDNA deletions. Deletion patterns also point to active mtDNA replication but little or no purifying selection against deleted mtDNA by mitophagy in postmitotic muscle fibers. Monte Carlo simulations of varied hypotheses for deletion formation, based in part on competing models of mtDNA replication, suggest the observed patterns are most consistent with deletions initiated by replication fork stalling during strand displacement mtDNA synthesis. Note that sequence data for HEK293 can be found under BioProject PRJNA642884.

  Study phs002052

• Rare Diseases Clinical Research Network (RDCRN) Vasculitis Clinical Research Consortium (VCRC) Longitudinal Protocol for Takayasu's Arteritis

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

  Study phs000589

• Type 1 Diabetes Genetics Consortium (T1DGC): Copy Number Variant (CNV) Study

  Type 1 Diabetes Genetics Consortium (T1DGC) was formed to address issues of limited sample size and consistency of phenotyping that had limited genetic investigations on risk of type 1 diabetes (T1D). The T1DGC first collected affected sib pair (ASP) families from four geographic networks (Asia-Pacific, Europe, North America, United Kingdom). In addition, T1D parent-offspring trios as well as cases and controls were ascertained from existing and de novo collections. For T1D, the genome-wide association study (GWAS) design has been successful at detecting ~50 loci that contribute disease risk. However, in the case of T1D as well as almost all other traits, the sum of these loci does not fully explain the heritability estimated from familial studies. One possibility for the undiscovered contribution to familial aggregation is that additional variants exist but have not yet been found because they have not effectively been targeted by the GWAS design. In this study, we focus on a specific class of large deletions/duplications -- copy number variants (CNVs) - and particularly to the subset of these loci that mutate rapidly, are not tagged by SNPs, and are highly polymorphic. The T1DGC assembled 2,601 T1D ASP families and 69 Parent-T1D offspring trios, that were eligible for this study. All samples included in this series have reported or self-declared European ancestry. All DNA samples were collected after approval from relevant institutional research ethics committees. Importantly, the source of DNA for CNV evaluation was uniform within a family (either all from PBMC or from EBV-transformed cell lines). We use a family based design that was optimized to capture these previously untested variants. We then perform a genome-wide scan to assess their contribution to T1D.

  Study phs000910

• The Role of Germline Mutation and Parental Age in Autism Spectrum Disorders

  <p>We will apply whole genome sequencing of trio families to determine how patterns of germline mutation throughout the genome determine risk for Autism Spectrum Disorder (ASD). We will investigate the nature intrinsic hypermutability and the extrinsic forces, such as paternal age, that influence rates of germline mutation. We will accomplish these goals through the following specific aims: Specific Aim 1 will characterize germline de novo mutations (DNMs) by whole genome sequencing in families. These studies will identify and validate ~8,000 de novo point mutations and structural variants in trios and controls to determine the parent of origin of DNMs. Specific Aim 2 will identify hot spots for germline mutation based on the regional density of DNMs in the genome, and determine the effects of DNA sequence features on rates of mutation. We will determine the association of mutation hotspots with ASD in the discovery sample and in genomic datasets from an independent sample of 2700 cases and 2700 controls. Specific Aim 3 will characterize the effects of extrinsic factors, including parental age and environment, on genome-wide rates of mutation. We will quantify the effect of paternal age on pathogenic and neutral alleles in sperm and investigate whether some DNMs confer a germline selective advantage. The findings of this study will provide fundamental insights into the genetic basis of autism risk and the genetic mechanism of the observed parental age effects in ASD. We will identify genes that confer significant risk for autism, and we will determine how intrinsic properties of the genome interact with extrinsic forces to determining risk for disease in offspring.

  Study phs001164

• Genotyping NIGMS CEPH Samples from the United States, Venezuela, and France

  The Human Genetic Cell Repository (HGCR) is sponsored by the National Institute of General Medical Sciences (NIGMS) with the mission of supplying scientists with the materials for accelerating disease gene discovery and functional studies. The resources available include highly-characterized, contaminant-free fibroblast cell lines, transformed lymphoblastoid cell lines (LCLs), and DNA samples derived from these cultures. While the Repository has a major emphasis on inherited diseases, it also contains large collections of cell lines gathered from populations around the world that are intended for use in facilitating the understanding of human variation. Prominent among these resources is the CEPH Reference Family collection contributed by the Centre d'Etude du Polymorphisme Humain (CEPH), Foundation Jean Dausset, Paris, France. The CEPH collection includes families collected by R. White (Utah), J. Dausset (French), J. Gusella (Venezuelan), and J. Egeland (Amish). There are a total of 809 individuals accounting for 832 pedigree positions in the reference families. Family relationships for the 61 reference families were verified at Coriell and approved by CEPH. In an effort to enhance the value of this cell culture resource available from the Repository, the Coriell Genotyping and Microarray Center used the Affymetrix Genome-Wide Human SNP Array 6.0 platform to genotype 181 samples from the NIGMS HGCR CEPH collection. Included are thirteen families from the United States (Amish Pedigree 884 and Utah Pedigrees 1331, 1356, 1400, 1416, 1424, 1427, 1477, and 1582), France (Pedigrees 35 and 66), and Venezuela (Pedigrees 102 and 104). Twelve of the families consist of 3 generations and one family consists of 2 generations. Pedigree charts and sample descriptions are available on the Repository catalog website (see below).

  Study phs000268

• The ClinSeq Project: Piloting Large-Scale Genome Sequencing for Research in Genomic Medicine

  ClinSeq is a pilot project to investigate the use of whole-genome sequencing as a tool for clinical research. By piloting the acquisition of large amounts of DNA sequence data from individual human subjects, we are fostering the development of hypothesis-generating approaches for performing research in genomic medicine, including the exploration of issues related to the genetic architecture of disease, implementation of genomic technology, informed consent, disclosure of genetic information, and archiving, analyzing, and displaying sequence data. In the initial phase of ClinSeq, we are enrolling roughly 1000 participants; the evaluation of each includes obtaining a detailed family and medical history, as well as a clinical evaluation. The participants are being consented broadly for research on many traits and for whole-genome sequencing. Initially, Sanger-based sequencing of 300-400 genes thought to be relevant to atherosclerosis is being performed, with the resulting data analyzed for rare, high-penetrance variants associated with specific clinical traits. The participants are also being consented to allow the contact of family members for additional studies of sequence variants to explore their potential association with specific phenotypes. Here, we present the general considerations in designing ClinSeq, preliminary results based on the generation of an initial 826 Mb of sequence data, the findings for several genes that serve as positive controls for the project, and our views about the potential implications of ClinSeq. The early experiences with ClinSeq illustrate how large-scale medical sequencing can be a practical, productive, and critical component of research in genomic medicine. Reprinted from Genome Res. 2009 Sep; 19(9): 1665-1674, with permission from Genome Research, PMID: 19602640.

  Study phs000971

• Columbia University Study of Caribbean Hispanics with Familial and Sporadic Late Onset Alzheimer's disease

  Compared to Caucasians residing in the same community the incidence rate of Alzheimer's disease is approximately twice as high in Caribbean Hispanics. Moreover, Caribbean Hispanics represent a homogenous population with only a few founders. Replication of genetic associations in other ethnic groups provides supporting evidence that a putative gene is involved in the disease pathogenesis, and when different allelic variants within the same genes are associated with disease it can help to localize the pathogenic variant. SORL1 is an example of a candidate gene that was first identified in Hispanics and then confirmed in multiple ethnic and racial groups in a meta-analysis. For this project, we are genotyping 704 individuals in families multiply affected by Alzheimer's disease (166 families). These families were recruited in the United States, Puerto Rico and the Dominican Republic. In addition, we are genotyping 2491 individuals (960 patients with sporadic Alzheimer's disease and 1531 unrelated controls) phenotyped in a similar fashion totaling 3195 individuals. Both cohorts are followed at regular intervals of 18 to 24 months, and potential phenotypes available other than those related to Alzheimer's disease include body mass index, measured blood pressure, neurological history and examinations. More importantly, both studies are funded through 2014 and additional phenotypes could be added in successive waves. We propose a genome wide association (GWA) study of Alzheimer's disease and longitudinal changes in cognition and other age-related neurological and medical phenotypes. The goal will be to identify the chromosomal locations of genes underlying this disease and its related endophenotypes.

  Study phs000496

• Research in Adaptive Interests, Skills, and Environment

  The Research on Adaptive Interest, Skills, and Environments (RAISE) project is a coordinated set of pilot studies funded and otherwise supported by the Center for the Study of Adolescent Risk and Resilience (C-StARR) at Duke University. The initial data collection effort (Adolescent T1; 2015; NAHDAP 100737) was conducted by telephone and focused on self-regulation and related skills during early adolescence and their role in early instances of health risk behavior. The survey was comprised of brief measures of constructs in six areas of interest to C-StARR investigators: (1) background and home environment; (2) self-regulation and personality; (3) physical and mental health; (4) problem behaviors; (5) academics and school; and (6) technology use. The representative sample of 2104 adolescents was drawn from the population of fifth through eighth graders enrolled in North Carolina public schools during the 2014-2015 school year.In 2016, a subsample of 395 participants from the Adolescent T1 survey (selected on the basis of having resided within 100 miles of study personnel hubs in Durham, North Carolina and Sylva, North Carolina) participated in an additional home visit study that involved the collection of biological data and measures of cognitive ability and executive functioning. The molecular data made available to dbGaP were obtained from saliva samples that were collected (a) in person from 377 of 395 home visit study participants and (b) by mail from 60 participants who had participated in the Adolescent T1 survey but had not participated in the home visit study. The resulting data file was imputed to a 1000G phase 3 panel and is comprised of N = 437 individuals and 7,193,135 markers after filtering. Data were filtered with MAF ≥ 0.01, HWE p-value > 10-6, and genotype rate > 95%.

  Study phs003982

• Confronting historical legacies of biological anthropology in South Africa—Restitution, redress and community-centered science: The Sutherland Nine

  We describe a process of restitution of nine unethically acquired human skeletons to their families, together with attempts at redress. Between 1925–1927 C.E., the skeletonised remains of nine San or Khoekhoe people, eight of them known-in-life, were removed from their graves on the farm Kruisrivier, near Sutherland in the Northern Cape Province of South Africa. They were donated to the Anatomy Department at the University of Cape Town. This was done without the knowledge or permission of their families. The donor was a medical student who removed the remains from the labourers’ cemetery on his family farm. Nearly 100 years later, the remains are being returned to their community, accompanied by a range of community-driven interdisciplinary historical, archaeological and analytical (osteobiographic, craniofacial, ancient DNA, stable isotope) studies to document, as far as possible, their lives and deaths. The restitution process began by contacting families living in the same area with the same surnames as the deceased. The restitution and redress process prioritises the descendant families’ memories, wishes and desire to understand the situation, and learn more about their ancestors. The descendant families have described the process as helping them to reconnect with their ancestors. A richer appreciation of their ancestors’ lives, gained in part from scientific analyses, culminating with reburial, is hoped to aid the descendant families and wider community in [re-]connecting with their heritage and culture, and contribute to restorative justice, reconciliation and healing while confronting a traumatic historical moment. While these nine individuals were exhumed as specimens, they will be reburied as people.

  Study EGAS50000000971

• UK10K NEURO EDINBURGH

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. This sample set consists of subjects with schizophrenia recruited from psychiatric in-patient and out-patient facilities in Scotland. All diagnoses are based on standard research procedures and family histories are available. Patients have IQ>70 and the cohort includes the following groups: 100 cases with detailed clinical, cognitive and structural and functional neuroimaging phenotypes; 138 familial cases who are the probands of families where DNA has been collected from other affected members; 162 unrelated individuals. In most cases patients and their families may be re contacted to take part in further studies.For further information on this cohort please contact Andrew McIntosh (andrew.mcintosh@ed.ac.uk).

  Study EGAS00001000117