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• Arcagen – thoracic malignancies

  Arcagen is an EORTC/SPECTA pan-European project that aims to recruit 1000 rare cancer patients from different tumour domains of EURACAN. This study collected samples from advanced or metastatic rare cancer from patients older than 12, and analysed them using Foundation Medicine next-generation sequencing (NGS) panels (FoundationOne CDx for FFPE samples or FoundationOne Liquid CDx for blood samples). Here we are submitting the dataset that contain NGS files from rare thoracic malignancies (n=102)

  Dataset EGAD50000000168

• Gene Expression and Epigenetic Analyses of Human Myocytes From Different Muscles

  The study contains expression and DNA methylation data of in vitro cultured myoblasts derived from biopsies of control, FSHD1 and FSHD2 patients from the tibialis anterior, quadricep, bicep and deltoid. Expression data is from bulk RNA-seq using the SmartSeq2 protocol for days 0 and 5 of in vitro differentiation of primary myocytes from the bicep and deltoid of FSHD1 patients. DNA methylation data was produced using the TruSeq Methyl Capture EPIC kit (Illumina) for days 0, 3 and 12 of in vitro differentiation of primary myocytes from the tibialis anterior and quadricep of healthy individuals and FSHD2 patients.

  Study phs002554

• Smith-Lemli-Opitz Syndrome: A Longitudinal Clinical Study of Patients Receiving Cholesterol Supplementation

  Smith-Lemli-Opitz syndrome (SLOS) is a disorder of cholesterol production by the body. It is caused by changes in the DHCR7 gene, which is the blueprint for an enzyme called 7-dehydrocholesterol- delta7-reductase. This enzyme is necessary for the production of cholesterol by all cells in the body. People with SLOS often have malformations of major organs, slow growth, feeding difficulties and intellectual disability or learning problems. Because patients with SLOS cannot make enough cholesterol, it has been proposed that cholesterol supplementation (either with egg yolk or liquid suspensions of cholesterol) could help improve the symptoms of the disease. However, despite the widespread use of cholesterol supplementation, it is still not known whether it works or not. The study will try to provide an answer to this question by studying the disease and its progression while patients are receiving cholesterol. The clinical features of SLOS are thought to be related to low cholesterol and buildup of toxic cholesterol precursors (substances from which cholesterol is formed). But how exactly low cholesterol and toxic precursors contribute to the disease is poorly understood. This knowledge is critically important because it should help discover new therapeutic targets and develop treatments of the disease in the long run. The study will try to fill this gap with a comprehensive clinical and biochemical testing of the study participants over the course of several years. Last, a limitation of previous SLOS research studies has been their low number of participants. This is understandable because SLOS is a rare diseases and few research groups are working on it. However, in order to fully understand the disease, researchers need to study as many patients as possible. This study is unique in that it is run by a network of several highly specialized clinical research sites across the country. Having several sites involved increases the researcher's ability to recruit and study large number of patients, and centralize patients' information in a comprehensive SLOS clinical registry. This registry will be key to identify markers for diagnostic testing, screening and measuring outcomes in future studies of treatment. The purpose of this study is to learn as much as possible about Smith-Lemli-Opitz Syndrome (SLOS) by following a large group of affected children and adults over time. In this study, we will measure cholesterol and other similar chemicals in blood and urine, evaluate development and behavior, do limited medical evaluation, and carry out brain imaging studies.This study will help researchers: learn more about what causes SLOS and how SLOS changes with age, note differences in features of SLOS among those affected, evaluate the effect of giving extra cholesterol in this condition, and develop ways to evaluate whether treatments developed in the future will be helpful.

  Study phs001430

• Polygenic Risk Score for the Prediction of Breast Cancer Is Related to Lesser Terminal Duct Lobular Unit Involution of the Breast

  The Susan G. Komen Tissue Bank (KTB) at the Indiana University Simon Cancer Center is an annotated biobank, which has recruited healthy women who provided demographic, lifestyle, and cancer-related information via self-administered questionnaire, blood samples and normal breast tissues. H&E slides of the normal breast tissues were scanned for image analysis and a pathologist measured the number of terminal duct lobular units (TDLUs) ("TDLU count"). The acini count per TDLU was quantified using the TDLU analyzer software. In this analysis, we computed the recently developed polygenic risk score (PRS) based on 313 common variants for the prediction of breast cancer and related this PRS to TDLU count and acini count per TDLU. We did this for the overall PRS, the ER-positive PRS and the ER-negative PRS.

  Study phs002062

• Native American gene flow into Polynesia predating Easter Island settlement

  The possibility of voyaging contact between prehistoric Polynesian and Native American populations has long intrigued researchers. Proponents have pointed to the existence of New World crops, such as the sweet potato and bottle gourd, in the Polynesian archaeological record, but nowhere else outside the pre-Columbian Americas while critics have argued that these botanical dispersals need not have been human mediated. The Norwegian explorer Thor Heyerdahl controversially suggested that prehistoric South American populations had an important role in the settlement of east Polynesia and particularly of Easter Island (Rapa Nui). Several limited molecular genetic studies have reached opposing conclusions, and the possibility continues to be as hotly contested today as it was when first suggested. Here we analyse genome-wide variation in individuals from islands across Polynesia for signs of Native American admixture, analysing 807 individuals from 17 island populations and 15 Pacific coast Native American groups. We find conclusive evidence for prehistoric contact of Polynesian individuals with Native American individuals (around AD 1200) contemporaneous with the settlement of remote Oceania. Our analyses suggest strongly that a single contact event occurred in eastern Polynesia, before the settlement of Rapa Nui, between Polynesian individuals and a Native American group most closely related to the indigenous inhabitants of present-day Colombia.

  Study EGAS00001004209

• The Multiomics Blueprint of the Individual with the Most Extreme Lifespan

  Although centenarians are becoming more common in the demography of human populations, the so-called supercentenarians (over 110 years old) are still a rarity. In Catalonia, the historic nation where the subject lived, the life-expectancy for women is 86 years old, so she exceeded more than 30 years the mean statistical value. In a similar manner that premature aging syndromes, such as Hutchinson-Gilford Progeria and Werner syndrome, can provide relevant clues about the mechanisms of aging; the study of supercentenarians might also shed light in the pathways involved in lifespan. To unfold the biological properties that exhibited such a remarkable human being, we developed a comprehensive multiomics analysis in different tissues of her genomic, transcriptomic, metabolomic, epigenomic and microbiomic landscapes , comparing the results with those observed in non-supercentenarian populations.

  Study EGAS50000000884

• Waldenström Macroglobulinemia Single-Cell Data Access Committee

  This Data Access Committee (DAC) is responsible for reviewing and approving access requests for controlled-access human single-cell sequencing data, including single-cell RNA sequencing and immune receptor profiling, generated from patients with Waldenström macroglobulinemia. The DAC ensures that all data access requests comply with the informed consent provided by study participants and are consistent with applicable ethical and regulatory requirements.

  Dac EGAC50000000863

• Genomics of Circulating Tumor Cells

  Comprehensive analyses of cancer genomes in clinical settings promise to inform prognoses and guide the deployment of precise cancer treatments. A major barrier, however, is the inaccessibility of adequate metastatic tissue for accurate genomic analysis in prostate and other cancers. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming multiple technical hurdles. Here, we report an integrated process to isolate, qualify, and sequence whole exomes of CTCs with high fidelity, using a census-based sequencing strategy. Power calculations suggest that mapping of over 99.995% of the territory accessible in bulk exome sequencing is possible in CTCs. We validated our sequencing process in two prostate cancer patients including one for whom we compared CTC-derived mutations to mutations found in a lymph node metastasis and nine cores of the primary tumor. 51 of 73 CTC mutations (70%) were observed in matched tissue. Moreover, we identified 10 early trunk mutations and 56 metastatic trunk mutations in the non-CTC tumor samples and found 90% and 73% of these, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic.

  Study phs000717

• A_systems_biology_approach_to_understand_immunity_and_pathogenesis_of_malaria_in_children_exposed_to_endemic_Plasmodium_falciparum_transmission

  From long-term studies of children in Kenya, we know that some children have numerous malaria episodes through to older age, while other children become immune more rapidly. Our hypothesis is that these children with frequent malaria episodes are caught in a vicious circle, whereby malaria episodes lead to impaired immunity to malaria, which in turn leads to further episodes of malaria. We will therefore investigate immune responses in children with different life histories of malaria episodes. We will also include a group of children living in similar environmental conditions but who are completely unexposed to malaria. Aims: Using RNAseq we will characterise the transcriptome of a group of children with frequent and febrile malaria or infrequent/asymptomatic. These data will be combined with cytokine profiling data (NIMR) and used to build predictive models (Exeter). The predictions will be validated against a similar second group. A single snap shot of immune responses may represent only the endpoint of many immune processes and may not reflect those that are causally related to differences in malaria outcome. Therefore, we will collect and store samples from a larger group of children who will then be followed up for over 3-4 years. This extended follow up will allow us to identify the same groups as described above, and then examine samples taken before the development of those outcomes. 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 EGAS00001002978

• Single cell sequencing reveals the origin and the order of mutation acquisition in T-cell acute lymphoblastic leukemia.

  Next-generation sequencing has provided a detailed overview of the various genomic lesions implicated in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL). Typically, 10 to 20 genomic lesions are found in T-ALL cells at diagnosis. However, it is currently unclear in which order these mutations are acquired and in which progenitor cells this is initiated. To address these questions, we used targeted single-cell sequencing of total bone marrow cells and CD34+CD38- multipotent progenitor cells for 4 T-ALL cases. Hierarchical clustering detected a dominant leukemia clone at diagnosis, accompanied by a few subclones harboring only a fraction of the mutations. We developed a graph-based algorithm to determine the order of mutation acquisition. Two of the four patients had an early event in a known oncogene (MED12, STAT5B) amongst various pre-leukemic events. Intermediate events included loss of 9p21 (CDKN2A/B) and acquisition of fusion genes, while NOTCH1 mutations were typically late events. Analysis of CD34+CD38- cells and myeloid progenitors revealed that in half of the cases somatic mutations were detectable in multipotent progenitor cells. We demonstrate that targeted single cell sequencing can elucidate the order of mutation acquisition in T-ALL and that T-ALL development can start in a multipotent progenitor cell.

  Study EGAS00001002830

• NHLBI GO-ESP: Lung Cohorts Exome Sequencing Project (Asthma): Genetic variants affecting susceptibility and severity

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. The exome sequencing asthma project includes 200 African-Americans with asthma from the NHLBI multicenter Severe Asthma Research Program (SARP). SARP participants were recruited at the NHLBI SARP sites with an emphasis on recruiting severe asthmatics (Moore et al., Am J Respir Crit Care Med, 2010. PMID: 19892860). Asthma status was based on both a physician's diagnosis and either bronchodilator reversibility or hyper-responsiveness to methacholine as well as less than 5 pack years of smoking. All subjects were carefully characterized using the standardized SARP protocol which included spirometry (medication withheld), maximum bronchodilator reversibility, hyper-responsiveness to methacholine (not performed in subjects with low baseline FEV1), skin-tests to common allergens, questionnaires on health care utilization and medication use and sputum, lung imaging and bronchoscopy in a subset. In addition GWAS data are available (phs000355, Illumina platform).

  Study phs000422

• Unraveling mutagenic processes influencing the tumor mutational patterns of individuals with Constitutional Mismatch Repair Deficiency

  Constitutional mismatch repair deficiency (CMMRD), caused by bi-allelic germline variants in one of the mismatch repair (MMR) genes, is a childhood cancer predisposition syndrome that often results in the development of multiple tumors early in life. A better understanding of mutational processes driving subsequent CMMRD tumors could advance optimal treatment. Therefore, we performed a genomic characterization of 41 tumors from 17 individuals with CMMRD. Mutational patterns in these tumors were found to be influenced by multiple factors, including the affected MMR genes, tumor types and somatic polymerase proofreading mutations. Temozolomide treatment left prominent mutational signatures in two second primary hematologic malignancies. Furthermore, a novel indel signature was found in 54% of the tumors, characterized by one base pair cytosine insertions in cytosine homopolymers. In conclusion, the analysis of sequential tumors in individuals with CMMRD reveals diverse mutational patterns influenced by the underlying mutated MMR gene, tumor type and treatment history.

  Study EGAS00001007660

• Multi-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions(H021/INF)

  Many rare cancers are not well understood, and pathogenesis-directed therapies are often lacking, resulting in poor patient outcomes. Leveraging two (inter)national precision oncology trials that enroll large numbers of rare cancers, we investigated the clinical, histopathologic, molecular, and functional characteristics of rhabdomyosarcoma (RMS) with fusions of FUS or EWSR1 to the TFCP2 transcription factor, a recently discovered ultra-rare entity whose classification, pathogenesis, and optimal treatment are unclear. Unusually for fusion-driven sarcomas, most cases had highly rearranged genomes, including chromothripsis, and signs of defective homologous recombination DNA repair. All tumors showed extreme expression of a truncated TERT variant and the ALK receptor tyrosine kinase, which was additionally affected by intragenic deletions and aberrant splicing, resulting in the expression of shortened variants in 58% of cases. Three ALK variants were oncogenic in immortalized cells, and patient-derived tumor cells expressing two variants responded to certain ALK inhibitors. Other recurrent alterations included CDKN2A/MTAP co-deletions and mutations in PAPPA2, encoding an IGFBP5-specific proteinase, in 67% and 25% of cases, respectively. DNA methylation analysis, along with 19 other soft-tissue sarcoma classes, revealed a close relationship with undifferentiated sarcoma but not other RMS subtypes, suggesting that TFCP2-rearranged RMS is a separate entity, possibly arising from a distinct cell of origin. Expression of TFCP2 fusions in immortalized human cells blocked late myogenic differentiation and significantly induced genes that were also highly expressed in patient tumors, including ALK, TERT, and two known regulators of skeletal muscle cells, IGFBP5 and PTH1R. Genome-wide chromatin profiling demonstrated direct binding of FUS-TFCP2 to the ALK and TERT loci outside their regular promoters, which correlated with the expression of alternative transcript variants. Finally, FUS-TFCP2 inhibited the repair of DNA double-strand breaks in immortalized cells, rendering them sensitive to treatment with cisplatin. This study provides insight into the pathogenesis and therapeutic vulnerabilities of a new RMS subtype and illustrates the value of linking comprehensive molecular diagnostics and functional annotation within multicenter consortia to improve the understanding and clinical management of rare cancers.

  Study EGAS00001006939

• Liquid Biopsy Detection of Tumor-specific Structural Variants in High Grade Serous Ovarian Cancer

  WGS Liquid Biopsy. Recurrence is frequent for most patients with high grade serous ovarian cancer (HGSOC), even after effective chemotherapy induced remission. However, after achievement of complete clinical response, the minimal residual disease is often insufficient for genomic analysis. Therefore, methods to interrogate the clonal composition and molecular properties of minimal residual disease are needed to better understand the mechanisms of HGSOC relapse. To address this unmet need, we developed and validated a novel cfDNA-based approach for tracking disease burden using NGS-informed tumor specific structural variants (SVs). Methods: The optimization of the methodology was first performed using synthetic cfDNA generated by ultrasonication of gDNA from ovarian cancer cell lines. Following the optimized workflow, whole genome sequencing of multisite biopsies from pre-treatment HGSOC patients were performed and high confidence SVs were called by consensus of multiple published SV callers. Real-time PCR and digital droplet PCR (ddPCR) were used for assays development.

  Study EGAS50000001044

• PREDICT-HD Huntington Disease Study

  The purpose of this project is to make clinical measurements from the PREDICT-HD consortium available through the dbGaP mechanism. The phenotype data will first be converted into a community open standard and subsequently exported to dbGaP for archival and open access distribution of the results of the studies. This will permit members of the scientific community to utilize a permanent resource for investigating the interactions of phenotypes upon an international cohort of early Huntington Disease. In version 2 cut of the data we provided HD CAG repeat lengths for both alleles as well as enrollment age of all participants. We have also generated unique identifiers prospectively compatible with the larger initiative GWAS in Huntington's Disease project (also on DbGaP). As such, the version 1 cut of the data was mainly proof of concept and should be deprecated. Going forward, all updates will add-on to version 2 cut of the data. In version 3 cut of the data, we provided baseline or the first usable MRI T1-weighted imaging analysis subcortical and cortical segmentations and cortical parcellations based on a customized Freesurfer 5.2 pipeline developed at The University of Iowa. The customizations to the standard pipeline were mainly to improve bias field correction and image normalization such that segmentation of gray, white, internal csf, dura and surface CSF are optimized for the Freesurfer pipeline. There are 1111 subjects with results in this data release. In version 4 cut of the data, we provided all longitudinal clinical measurements for all subjects (total of 1476) assessmented or enrolled through the end of 2013. Additionally, we are providing measurements on 39 baseline FDG PET images spatially normalized by SPM5 into MNI space, relative regional metabolic values computed in 120 volumes of interest (VOI) defined in the Automated Anatomical Labeling (AAL) Atlas (Tzourio-Mazoyer et al. 2002), and global metabolic values calculated by SPM standard mean voxel value (within per image fullmean/8 mask). This project is a funded ancillary study of PREDICT-HD. In version 5 cut of the data, we provided the first of many forthcoming results from ancilliary studies of PREDICT-HD. In this data cut, we provide individual subject results derived from structural MRI data. The earliest MRI session for each subject was used. The results summarized represent source based morphometry loading coefficients for 23 components (see: "Patterns of Co-Occurring Gray Matter Concentration Loss across the Huntington Disease Prodrome", Ciarochi et al., 2016, Front Neurol. 2016; 7: 147, Published online 2016 Sep 21. doi: 10.3389/fneur.2016.00147]. In this version 6 cut of the data, we provide a full set of derived data, more than 10,000 raw MRI images, and ancillary study data sets. For sample information please link to: PREDICT-HD Biospecimen Resources

  Study phs000222

• Discovery of Colorectal Cancer Susceptibility Genes in High-Risk Families

  Colorectal cancer remains one of the most common cancers in the US with 146,970 new diagnoses and 49,920 deaths estimated for 2009. Colon cancer is also one of the most familial of cancers. Individuals with a first-degree relative with colon cancer have a 2- to 3-fold increased risk, and those with more than one first-degree relative with colon cancer, or a single first-degree relative affected at age 50 years, have a 3- to 6-fold greater risk than those with no family history. The most prominent high-risk colorectal cancer susceptibility genes, APC, MLH1, MSH2, MSH6, and PTEN, were all discovered more than a decade ago. Currently, mutation screening of these genes, plus a short list of additional genes that are responsible for a very small fraction of colorectal cancer, plays an important role in the clinical management of individuals with a strong family history of the disease or syndromic evidence for the presence of a gene mutation. At the other end of the risk spectrum, genome-wide association studies have identified a number of common alleles with very modest effects on colorectal cancer risk; their clinical utility has yet to be established. However, taken together, the known spectrum of genetic effects only explain about one quarter of the overall familial excess of colorectal cancer. It should be emphasized that, at present, the vast majority of individuals seen at familial cancer clinics are counseled on the basis of their family history alone because they do not have mutations in the known susceptibility genes. Accordingly, the long-term objective of this project is to identify the majority of genes responsible for the unexplained component of inherited colorectal cancer risk. Nextgen DNA sequencing is well suited for application to research questions in genetic susceptibility for which linkage analysis is confounded by extensive genetic heterogeneity. Taking advantage of unparalleled familial cancer genetics resources available through the Utah Population Database, candidate genes have been identified by sequencing all of the gene exons in the human genome from a series of colorectal cancer cases with a very strong family history of colorectal cancer not explained by one of the currently known high-risk susceptibility genes.

  Study phs001787

• Combined Targeting of CDK4/6 and HER2 Signaling in Orthotopic Patient-Derived Xenografts of HER2-Positive Breast Cancer Brain Metastases

  Patients with metastatic HER2-positive (HER2+) breast cancer will frequently develop brain metastases (BCBMs). Here, we report that p16INK4A, a tumor suppressor, is deficient in the majority of HER2+ BCBMs. Furthermore, p16INK4A deficiency, as measured by protein immunohistochemistry, can be a predictive marker associated with response to combined treatment with tucatinib and abemaciclib in our orthotopic patient-derived xenografts (PDXs) models of HER2+ BCBMs. Our findings provide the rationale for a biomarker-driven clinical trial of combined treatment with CDK4/6- and HER2-targeted agents for patients with HER2+ BCBM.  

  Study phs002482

• South African breast cancer GWAS genotype data in VCF format

  South African breast cancer GWAS genotype data for 2823 female African breast cancer cases. The data was generated using the H3Africa Custom microarray and genotyped on the Illumina HiScan instrument. The dataset is in VCF format.

  Dataset EGAD00010002732

• Multi-omic analyses from a randomized phase II study of epigenetic priming followed by nivolumab in previously treated metastatic non-small cell lung cancer

  Emergence of resistance to immune checkpoint blockade (ICB) mandates the development of strategies for ICB sensitization. We aimed to understand the effects of epigenetic priming in re-shaping the tumor microenvironment, together with molecular drivers of therapeutic response of epigenetic therapy followed by ICB in non-small cell lung cancer (NSCLC; NCT01928576). This was done through a multi-omic approach encompassing both genomic and transcriptomic analyses. Findings suggest that epigenetic therapy may reshape the tumor microenvironment towards a more inflamed phenotype and prime responses to immunotherapy.

  Study EGAS50000000913

• Nasopharynx Cancer Whole Exome Sequencing

  Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression, and rational therapy design. Here, we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-kB pathway in a total of 41% of cases including CYLD, TRAF3, NFKBIA and NLRC5. Functional analysis confirmed novel inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent member protein 1 (LMP1) functions to constitutively activate NF-kB signaling, and we observed mutual exclusivity among somatic NF-kB pathway aberrations and LMP1-overexpression, suggesting that NF-kB activation is selected for by both somatic and viral events during NPC pathogenesis.

  Study phs001244

• A Genome-Wide Association Study in Breast Cancer Patients from the Prospectively Randomized SUCCESS Trial

  The SUCCESS-A Study (http://www.success-studie.de) is a randomized Phase III study of response to treatment of early primary breast cancer with adjuvant therapy after surgical resection. The primary outcome is disease-free survival and secondary outcomes are overall survival and toxicity. The study design includes comparison of two pairs of treatment regimes performed in sequence. The first randomization contrasts treatment with and without Gemcitabine (3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide(FEC)-chemotherapy, followed by 3 cycles of Docetaxel(D)-chemotherapy versus 3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide(FEC), followed by 3 cycles of Gemcitabine-Docetaxel(DG)-chemotherapy). The second randomization contrasts treatment with Zoledronate for two versus five years. Patients were recruited from 2005 to 2007 and a total of 3754 patients were included from 250 study sites across Germany. Genome-wide SNP microarray data and phenotype outcomes for the first phase of the study (treatment with and without Gemcitabine) are included in the GARNET (Genomics and Randomized Trials Network) pharmacogenomic study in this dbGaP submission. (The Zoledronate treatments are still underway). SUCCESS-A is a an open-label, multicenter, 2x2 factorial design, randomized controlled, Phase III study comparing the disease free survival after randomization in patients treated with 3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide(FEC)-chemotherapy, followed by 3 cycles of Docetaxel(D)-chemotherapy versus 3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide(FEC), followed by 3 cycles of Gemcitabine-Docetaxel(DG)-chemotherapy, and to compare the disease free survival after randomization in patients treated with 2 years of Zoledronate versus 5 years of Zoledronate in patients with early primary breast cancer. Patients were required to have histopathological proof of axillary lymph node metastases (pN1-3) or high risk node negative, defined as: pT>2 or histopathological grade 3, or age , ≤ 35 or negative hormone receptor, but were not allowed to have evidence of distant disease. Patients were entered into the study no later than 6 weeks after complete resection of the primary tumor. No antineoplastic treatment other than surgical treatment, the defined cytotoxic and endocrine treatment, and radiotherapy was allowed prior to study entry and during the course of the study. After surgery, leading to complete resection of the invasive and intraductal components of the primary tumor, patients were randomized to one of the following two treatments for the first phase of the project (which is included in this GARNET pharmacogenomics study): AA: 3 cycles of 5-Fluorouracil 500 mg/m² i.v. body surface area and Epirubicin 100 mg/m² i.v. and Cyclophosphamide 500 mg/m² i.v., (FEC100), each administered on day 1, repeated on day 22, subsequently followed by 3 cycles of Docetaxel 75 mg/m² body surface area i.v. (D), and Gemcitabine 1000 mg/m² i.v. (30 min infusion) (G), administered on day 1, followed by Gemcitabine 1000 mg/m² i.v. (30 min infusion) on day 8, repeated on day22 AB: 3 cycles of 5-Fluorouracil 500 mg/m² i.v. body surface area and Epirubicin 100 mg/m² i.v. and Cyclophosphamide 500 mg/m² i.v., (FEC100), each administered on day 1, repeated on day 22, subsequently followed by 3 cycles of Docetaxel 100 mg/m² body surface area i.v. (D), administered on day 1, repeated on day 22 A second randomization was made for assigning patients to one of the following two subsequent treatments for the second phase of the project (NOT included in the pharmacogenetic study in this dbGaP submission): BA: Zoledronic acid 4 mg i.v., every 3 months for the duration of two years, subsequently followed by zoledronic acid 4 mg i.v., every 6 months for the duration of additional three years BB: Zoledronic acid 4 mg i.v., every 3 months for the duration of two years Patients with positive hormone receptor status (≥10% positively stained cells for estrogen and/or progesterone) of the primary tumor were recommended to receive Tamoxifen treatment 20 mg p.o. per day for 2 years, after the end of chemotherapy . Subsequent to chemotherapy, postmenopausal patients with positive hormone receptor status were recommended to be treated with Anastrozole (Arimidex®) 1 mg p.o. for additional 3 years, premenopausal patients will continue Tamoxifen treatment for those additional 3 years. In addition to tamoxifen, all patients with positive hormone receptor status of the primary tumor and under the age of 40 or restart of menstrual bleeding within 6 months after the completion of cytostatic treatment or with premenopausal hormone levels as defined below were recommended to receive Goserelin (Zoladex®) 3.6 mg subcutaneously every 4 weeks over a period of 2 years following chemotherapy. Premenopausal endocrine status will be assumed, if the following serum levels are met: LH < 20 mIE/ml, FSH < 20 mIE/ml and E2 > 20 pg/ml. Endocrine therapy will start after the end of chemotherapy. All patients with breast conserving therapy or more than 3 axillary lymph node metastases or in the following cases after mastectomy will receive adjuvant radiotherapy: T3/T4-carcinoma, T2-carcinoma > 3 cm, multicentric tumor growth, lymphangiosis carcinomatosa or vessel involvement, involvement of the pectoralis fascia or a safety margin < 5 mm. Radiotherapy was usually performed after the chemotherapy and parallel to the beginning of the zoledronic acid therapy. Initially, DNA was extracted for performing SNP microarray assays using blood collected at baseline prior to the first randomization. However, the first set of SNP microarray results indicated a quality problem with approximately 50% of the DNA samples. A majority of the problematic samples were replaced with DNA extracted from redrawn blood. The remaining problematic samples were 'restored' using an Illumina FFPE Restoration procedure. A total of 3322 subjects (1638 from arm AA and 1684 from arm AB) were successfully genotyped. Among those, 1771 were from original blood samples, 1092 from redrawn blood samples and 459 from restored blood samples. The SUCCESS-A study is part of the Genomics and Randomized Trials Network (GARNET, http://www.garnetstudy.org) funded by the National Human Genome Research Institute (NHGRI). The overarching goal is to identify novel genetic factors that contribute to disease-free survival for breast cancer patients using different forms of chemotherapy through large-scale genome-wide association studies of treatment response in randomized clinical trials. The study was conducted at the University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Germany. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were performed at the GARNET Coordinating Center at the University of Washington.

  Study phs000547

• Whole genome sequencing with linked reads of pediatric glioblastoma samples

  Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. To understand mechanisms of tumor evolution in this cancer, we performed whole genome sequencing with linked reads on longitudinally resected pGBM samples. Our analyses showed that all diagnostic and recurrent samples were collections of genetically diverse subclones. Clonal composition rapidly evolved at recurrence, with less than 8% of non-synonymous single nucleotide variants being shared in diagnostic-recurrent pairs. In order to track the origins of the mutational events we observed in pGBM, we generated whole genome datasets for two patients and their parents. These trios showed that genetic variants could be (i) somatic, (ii) inherited from a healthy parent, or (iii) arose de novo in the germlines of pGBM patients. Analysis of variant allele frequencies supported a model of tumor growth involving slow-cycling cancer stem cells that give rise to fast-proliferating progenitor-like cells and to non-dividing cells. Interestingly, radiation and anti-mitotic chemotherapeutics did not increase overall tumor burden upon recurrence. These findings support an important role for slow-cycling stem cell populations in contributing to recurrences, since slow-cycling cell populations are expected to be less prone to genotoxic stress induced by these treatments and to accumulate few mutations. Our results highlight the need for new targeted treatments that account for the complex functional hierarchies and genomic heterogeneity of pGBM.

  Study EGAS00001003432

• Sleep Heart Health Study (SHHS-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions.Related StudiesParent cohort phenotype data can be accessed through ARIC-BioLINCC, Framingham-BioLINCC, and CHS-BioLINCC. Objectives To determine the cardiovascular and other consequences of sleep-disordered breathing and to test whether sleep-disordered breathing is associated with an increased risk of coronary heart disease, stroke, all-cause mortality and hypertension by examining subjects from well-characterized and established epidemiologic cohorts. Background Obstructive sleep apnea syndrome (OSA) is a potentially debilitating condition characterized by repetitive episodes of apnea while asleep, nocturnal oxygen desaturation, excessive daytime sleepiness, and loud disruptive snoring. Epidemiologic data from middle-aged adults indicate that OSA is common, with prevalence rates of 4% in men and 2% in women. Prior studies implicated OSA as a risk factor for the development of hypertension, ischemic heart disease, congestive heart failure, stroke and consequently premature death. Questions arose as to whether an increased propensity for cardiovascular and cerebrovascular diseases was limited to only those with frank OSA or whether more subtle forms of sleep-disordered breathing (SDB) would also confer elevated risk. Further evidence was also needed to clarify whether, SDB, including OSA, is an independent risk factor for the development of cardiovascular or cerebrovascular disease. Known cardiovascular and cerebrovascular disease risk factors such as obesity and smoking are commonly present in those with SDB; therefore, apparent associations between SDB and cardiovascular and cerebrovascular diseases may have resulted from the effects of these concomitant risk factors. Moreover, there was no understanding as to whether such factors as race, age, gender, and prevalent cardiovascular or cerebrovascular disease might interact with SDB to alter future cardiovascular and cerebrovascular disease risk. Mechanisms underlying any propensity to develop cardiovascular or cerebrovascular disease with SDB had not been firmly established (Quan, et al., 1997, PMID: 9493915). Participants Participants in SHHS were recruited from nine existing NHLBI epidemiological studies in which data on cardiovascular risk factors had been collected previously. The “parent” cohorts included: Two sites of the Atherosclerosis Risk in Communities Study (ARIC) Three sites of the Cardiovascular Health Study (CHS) The Framingham Offspring Cohort The Strong Heart Study (SHS) sites in South Dakota, Oklahoma, and Arizona The New York Hypertension Cohorts The Tucson Epidemiologic Study of Airways Obstructive Diseases and the Health and Environment Study From these parent cohorts, a sample of participants who met the inclusion criteria (age 40 years or older; no history of treatment of sleep apnea; no tracheostomy; no current home oxygen therapy) was invited to participate in the baseline examination of the SHHS, which included an initial polysomnogram (SHHS-1). Several cohorts over-sampled snorers in order to increase the study-wide prevalence of sleep-disordered breathing. In all, 6441 individuals were enrolled between November 1, 1995 and January 31, 1998. During exam cycle 3 (January 2001-June 2003), a second polysomnogram (SHHS-2) was obtained in 3295 of the participants. Due to sovereignty issues, Strong Heart Study participants are not included in the shared SHHS data. Data from a total of 5839 participants (1920 ARIC, 1249 CHS, 997 Framingham Offspring and OMNI 1, and 1673 from other studies), consenting to share data are available. Design The Sleep Heart Health Study added in-home polysomnography to the data collected in each of the parent studies at a baseline SHHS exam and a follow-up approximately 4 years later. Using the Compumedics PS polysomnograph, sleep studies were obtained in an unattended setting, usually in the homes of the participants, by trained and certified technicians. The recording montage consisted of: C3/A2 and C4/A1 EEGs, sampled at 125 Hz right and left electrooculograms (EOGs), sampled at 50 Hz a bipolar submental electromyogram (EMG), sampled at 125 Hz thoracic and abdominal excursions (THOR and ABDO), recorded by inductive plethysmography bands and sampled at 10 Hz "airflow" detected by a nasal-oral thermocouple (Protec, Woodinville, WA), sampled at 10 Hz finger-tip pulse oximetry (Nonin, Minneapolis, MN) sampled at 1 Hz ECG from a bipolar lead, sampled at 125 Hz for most SHHS-1 studies and 250 Hz for SHHS-2 studies Heart rate (PR) derived from the ECG and sampled at 1 Hz body position (using a mercury gauge sensor) ambient light (on/off, by a light sensor secured to the recording garment)This montage provides data on the occurrence of sleep-disordered breathing, sleep stages, heart rate, oximetry and on arousals. Each participant in the parent studies was also asked to complete the Sleep Habits Questionnaire which covers usual sleep pattern, snoring, and sleepiness.

  Study phs003637

• The variable genomic landscape during osteosarcoma progression: insights from a longitudinal WGS analysis

  Osteosarcoma is a primary bone tumor that exhibits a complex genome characterized by gross chromosomal abnormalities. Osteosarcoma patients often develop metastatic disease, resulting in limited therapeutic options and poor survival rates. To gain knowledge on the mechanisms underlying osteosarcoma heterogeneity and metastatic process, it is important to obtain a detailed profile of the genomic alterations that accompany osteosarcoma progression. Therefore, in this study we performed WGS on multiple tissue samples from six patients with osteosarcoma, including the treatment naïve biopsy of the primary tumor, resection of the primary tumor after neoadjuvant chemotherapy, local recurrence and distant metastases.

  Study EGAS50000000329

• Evolution and clinical impact of genetic epistasis within EGFR-mutant lung cancers: multi-timepoint exome sequencing of a single patient's disease

  This dataset is a time-series of EGFR-mutant NSCLC clinical specimens from an individual patient profiled using tumor-based whole exome sequencing and the data is in BAM format. DNA was extracted from FFPE for primary tumor and frozen tumor tissue samples and matched non-tumor tissue using the Qiagen Allprep DNA/RNA Mini Kit.  The library preparation protocol was based on the Agilent SureSelect Library Prep and Capture System. DNA was resuspended in a low TE buffer and sheared (Duty Cycle 5%; Intensity 175; Cycles/Burst: 200; Time: 300s, Corvaris S2 Utrasonicator).  Bar-coded exome libraries were prepared using the Agilent Sure Select V5 library kit per manfucaturer’s specifications. The libraries were run on the HiSeq2500. Raw paired end reads (100bp) in FastQ format generated by the Illumina pipeline were aligned to the full hg19 genomic assembly obtained from USCS, gencode 14, using bwa version 0.7.12. Picard tools version 1.117 was used to sort, remove duplicate reads and generate QC statistics. Tumor DNA was sequenced to median depth of 303X (range 114.39-383.41) and the matched germline DNA to average depth of 231.65.

  Dataset EGAD00001003769