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• PCGP Ph-like ALL

  Background: BCR-ABL1-like, or Ph-like acute lymphoblastic leukemia is characterized by a gene expression profile similar to BCR-ABL1 positive ALL, genetic alterations of lymphoid transcription factor genes, and poor outcome. Sequencing of small numbers of Ph-like ALL cases has identified genetic alterations activating kinase signaling suggesting Ph-like ALL may be amenable to treatment with tyrosine kinase inhibitors. However, the spectrum of genetic alterations in childhood and adult Ph-like ALL is incompletely understood. Methods: We performed genomic profiling of 1736 B-ALL cases and next-generation sequencing for 160 Ph-like cases. We examined the functional effects of chimeric fusion proteins in mouse cell lines. Results: The frequency of Ph-like ALL rose from 11% in children to 26% in young adults, and was associated with very poor outcome. Kinase-activating alterations were identified in 90% of Ph-like cases, most commonly fusions involving 10 kinase or cytokine receptor genes (ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B and TYK2), and mutations involving FLT3, IL7R and SH2B3. Expression of ABL1, ABL2, CSF1R and JAK2 fusions resulted in cytokine-independent proliferation of cell lines and activation of pSTAT5. Cells expressing ABL1, ABL2, CSF1R and PDGFRB fusions were sensitive to dasatinib, and JAK2 fusions to ruxolitinib. Conclusions: Ph-like ALL is characterized by a diverse range of genomic alterations that converge on a limited number of kinase signaling pathways amenable to inhibition with currently available tyrosine kinase inhibitors. Trials identifying Ph-like ALL and testing the efficacy of tyrosine kinase inhibitor therapy are warranted

  Study EGAS00001000654

• Genetic characterization of B-cell prolymphocytic leukemia: a hierarchical prognostic model involving MYC and TP53 abnormalities - RNA-seq

  B-cell prolymphocytic leukemia (B-PLL) is a rare disease, whose molecular pathology is largely unknown. We report here the cytogenetic and molecular findings in a large series of 34 B-PLL. Karyotype (K) was complex (≥3 abnormalities) in 73%, and highly complex (HCK≥5) in 45%. The most frequent chromosomal aberrations were: translocation targeting the MYC gene [t(MYC)] (62%), 17p deletion including TP53 gene (38%), trisomy 18/18q (30%), 13q14 deletion (29%), trisomy 3 (24%), trisomy 12 (24%) and 8p deletion (23%). Whole-Exome Sequencing performed in 16 patients revealed recurrent mutations in TP53 (6/16, 38%), MYD88 (n=4), BCOR (n=4), MYC (n=3), SF3B1 (n=3), FAT1 (n=3), SETD2 (n=2), CHD2 (n=2), CXCR4 (n=2) and BCLAF1 (n=2). The main group of patients (21/34, 62%) had a t(MYC) associated with a higher percentage of prolymphocytes (p=0.03), CD38 expression (p<0.001), lower K complexity (p=0.0004), mutations in MYC and in genes involved in RNA metabolism and chromatin remodeling. Principal component analysis of gene expression data showed that patients with t(MYC) clustered together. A second group with MYC gain (5/34, 15%), was associated with HCK≥5 (p=0,01) and trisomy 3 (p=0,008). Altogether, 26/34 patients (76%) had a MYC activation, translocation or gain, that were mutually exclusive. We identified 3 distinct cytogenetic prognostic groups (p=0.0006): lower risk: absence of MYC activation (median not reached); intermediate risk: MYC activation without del17p (125 months); high risk: MYC activation + del17p (11 months). Our results show that cytogenetic analysis is a useful diagnostic tool in B-PLL that improves prognostic stratification.

  Study EGAS00001003274

• IMCISION DNAseq

  Standard-of-care (SOC) surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) is intensive and results in 30‒50% five-year overall survival. Anti-PD1 immune checkpoint blockade (ICB) durably improves survival rates in recurrent/metastatic HNSCC. We report on the non-randomized phase Ib/IIa IMCISION trial (NCT03003637) of 32 HNSCC patients treated with two doses neoadjuvant nivolumab (NIVO MONO, n=6, phase Ib arm A) or two doses of nivolumab plus a single dose of ipilimumab (COMBO, n=26, 6 in phase Ib arm B and 20 in phase IIa) prior to surgery and, if indicated, adjuvant radiotherapy. Neoadjuvant ICB was feasible in all phase Ib patients, meeting the phase Ib primary feasibility endpoint. One phase IIa patient had progressive disease precluding surgery. Primary tumor pathological response (phase IIa primary endpoint), defined as the % change in viable tumor cells from baseline biopsy to on-treatment resection, was evaluable in 29 patients. . We observed a major pathological response (MPR, 90‒100% response) in 8/23 (35%) evaluable COMBO and 1/6 (17%) NIVO MONO patients. None of the patients with MPR after NIVO MONO or COMBO developed a tumor relapse after 24.0 months median follow-up. FDG-PET-based total lesion glycolysis identified MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia signature expression were observed in MPR patients. Our data indicate that neoadjuvant NIVO MONO and COMBO are safe in HNSCC, and that particularly COMBO ICB shows encouraging effectivity. IMCISION provides rationales for future HNSCC trials aiming to pre-operatively select patients with a likely MPR after neoadjuvant ICB for de-escalation of SOC.

  Study EGAS00001005466

• Whole Genome Bisulfite Sequencing of Circulating Cell-Free (CCF) DNA and its Cellular Contributors

  Background: Circulating cell free (ccf) fetal DNA has enabled non-invasive prenatal fetal aneuploidy testing without direct discrimination of the genetically distinct maternal and fetal DNA. Current testing may be improved by specifically enriching the sample material for fetal DNA. DNA methylation may allow for such a separation of DNA and thus support additional clinical opportunities; however, this depends on knowledge of the methylomes of ccf DNA and its cellular contributors. Results: Whole genome bisulfite sequencing was performed on a set of unmatched samples including ccf DNA from 8 non-pregnant (NP) and 7 pregnant female donors and genomic DNA from 7 buffy coat and 5 placenta samples. We found CpG cytosines within longer fragments were more likely to be methylated, linking DNA methylation and fragment size in ccf DNA. Comparison of the methylomes of placenta and NP ccf DNA revealed many of the 51,259 identified differentially methylated regions (DMRs) were located in domains exhibiting consistent placenta hypomethylation across millions of consecutive bases, regions we termed placenta hypomethylated domains. DMRs identified when comparing placenta to NP ccf DNA were recapitulated in pregnant ccf DNA, confirming the ability to detect differential methylation in ccf DNA mixtures. Conclusions: We generated methylome maps for four sample types at single base resolution, identified a link between DNA methylation and fragment length in ccf DNA, identified DMRs between sample groups, and uncovered the presence of megabase-size placenta hypomethylated domains. Furthermore, we anticipate these results to provide a foundation to which future studies using discriminatory DNA methylation may be compared.

  Study phs000846

• Blood DNA Methylation in Post-Acute Sequelae of COVID-19 (PASC): a Prospective Cohort Study

  Background: DNA methylation integrates environmental signals with transcriptional programs. COVID-19 infection induces changes in the host methylome. While post-acute sequelae of COVID-19 (PASC) is a long-term complication of acute illness, its association with DNA methylation is unknown. No universal blood marker of PASC, superseding single organ dysfunctions, has yet been identified. Methods: In this single center prospective cohort study, PASC, post-COVID without PASC, and healthy participants were enrolled to investigate their symptoms association with peripheral blood DNA methylation data generated with state-of-the-art whole genome sequencing (WGS). PASC-induced quality-of-life deterioration was scored with a validated instrument, SF-36. Analyses were conducted to identify potential functional roles of differentially methylated loci, and machine learning algorithms were used to resolve PASC severity. Findings: 103 patients with PASC (22.3% male, 77.7% female), 15 patients with previous COVID-19 infection but no PASC (40.0% male, 60.0% female), and 27 healthy volunteers (48.1% male, 51.9% female) were enrolled. Whole genome methylation sequencing revealed 39 differentially methylated regions (DMRs) specific to PASC, each harboring an average of 15 consecutive positions, that differentiate patients with PASC from the two control groups. Motif analyses of PASC-regulated DMRs identify binding domains for transcription factors regulating circadian rhythm and others. Some DMRs annotated to protein coding genes were associated with changes of RNA expression. Machine learning support vector algorithm and random forest hierarchical clustering reveal 28 unique differentially methylated positions (DMPs) in the genome discriminating patients with better and worse quality of life.

  Study phs003658

• NCI Cancer Model Development for the Human Cancer Model Initiative (HCMI)

  The Cancer Model Development Center (CMDC) project is part of the Human Cancer Model Initiative (HCMI) and is managed by the Office of Cancer Genomics within the Center for Cancer Genomics at the National Cancer Institute (NCI). The goal of the HCMI is to generate approximately 1000 novel human "next generation" tumor-derived models as a community resource. The models aim to faithfully recapitulate the cellular complexity and heterogeneity of human tumors. The CMDCs are tasked by the NCI with producing a proportion of the cancer models. Wellcome Sanger Institute (WSI) is a contributing member of the HCMI. Models developed by HCMI are being derived from a number of tumor types and subtypes (see below), including rare adult, pediatric and understudied cancers. The number of models and the clinical sites from which patient samples are acquired is increasing. Normal tissue, originating tumor, and tumor-derived models are sequenced. The next generation cancer models are associated with rich clinical and genomic data through the NCI Genomic Data Commons for all researchers to advance cancer research. The CMDC and HCMI models will serve as excellent tools in research to provide insight into the pathways that influence tumor growth and progression, how tumors respond to therapy, etc. Ultimately, the data generated using these models will support the development of personalized oncology. There is a delay between registered IDs and model availability. The current model count is found in The HCMI Searchable Catalog which is updated when new models are available for distribution to the research community.

  Study phs001486

• Colon Cancer Family Registry (Colon CFR)

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

  Study phs002733

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

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

  Study JGAS000346

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

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

  Study JGAS000327

• A Single Complex Agpat2 Allele In A Patient With Partial Lipodystrophy

  Genetic lipodystrophies are a group of rare syndromes associated with major metabolic complications - including severe insulin resistance, type 2 diabetes mellitus, and hypertriglyceridemia - which are classified according to the distribution of adipose tissue. Lipodystrophies can be present at birth or develop during life and can range from local to partial and general. With at least 18 different genes implicated so far, definite diagnosis can be challenging due to clinical and genetic heterogeneity. In an adult female patient with clinical and metabolic features of partial lipodystrophy we identified via whole genome sequencing a single complex AGPAT2 allele [V67M;V167A], functionally equivalent to heterozygosity. AGPAT2 encodes for an acyltransferase implicated in the biosynthesis of triacylglycerol and glycerophospholipids. So far homozygous and compound heterozygous mutations in AGPAT2 have only been associated with generalized lipodystrophy. A SNP risk score analysis indicated that the index patient is not predisposed to lipodystrophy based on her genetic background. The partial phenotype in our patient is therefore more likely associated to the genetic variants in AGPAT2. To test whether the resulting double-mutant AGPAT2 protein is functional we analysed its in vitro enzymatic activity via mass spectrometry. The resulting AGPAT2 double mutant is enzymatically inactive. Our data support the view that the current classification of lipodystrophies as strictly local, partial or generalized may have to be re-evaluated and viewed more as a continuum, both in terms of clinical presentation and underlying genetic causes. Better molecular understanding of lipodystrophies may lead to new therapies to treat adipose tissue dysfunction in common and rare diseases.

  Study EGAS00001003177

• Comparison of the diagnostic yield of aCGH and NGS across different neurodevelopmental disorders

  Current recommendations for the genetic diagnosis of neurodevelopmental disorders (NDDs) do not include the use of next generation sequencing (NGS) and are still based on chromosomal microarrays, such as comparative genomic hybridization array (aCGH). The present study compares the diagnostic yield obtained by aCGH and clinical exome sequencing in NDD globally and its spectrum of disorders. To that end, 1412 patients clinically diagnosed with NDDs and studied with aCGH were classified into phenotype categories: Global developmental delay/intellectual disability (GDD/ID); autism spectrum disorder (ASD); and Other NDDs. These categories were further subclassified into subcategories, based on the most frequent accompanying signs and symptoms: isolated forms, forms with epilepsy; forms with micro or macrocephaly and syndromic forms. A subset of 245 patients of the 1412 were subjected to clinical exome sequencing. Diagnostic yield of aCGH and clinical exome sequencing, expressed as the number of solved cases, was compared for each phenotype category and subcategory. Clinical exome sequencing was superior than aCGH for all cases except for isolated ASD, with no cases solved by NGS. Globally, clinical exome sequencing solved 20% of cases (versus 5.7% by aCGH) and the diagnostic yield was highest for all forms of GDD/ID and lowest for Other NDDs (7.1% versus 1.4% by aCGH) and ASD (6.1% versus 3% by aCGH). In the majority of cases, diagnostic yield was higher in the phenotype subcategories than in the mother category. These results support the use of NGS as the first-tier test in the diagnostic algorithm of all NDDs followed by aCGH when necessary.

  Study EGAS00001004949

• Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) was designed to evaluate the hypothesis that amiodarone or a conservatively programmed shock-only, single-lead implantable cardioverter defibrillator (ICD) would decrease the risk of death from any cause in a broad population of patients with mild-to-moderate heart failure. Background Patients with congestive heart failure (CHF) can die suddenly and unpredictably from arrhythmia despite the use of proven medical therapies, such as beta-blockade. Two approaches have been developed to prevent sudden death among patients with CHF: therapy with amiodarone and therapy with an ICD. However, most of the mortality data on amiodarone and ICD therapy at the time of the study had been obtained in clinical trials performed after myocardial infarction in patients without CHF or those with ventricular arrhythmias. Thus, more data was needed to guide these therapies in patients who did not meet these criteria. Participants There were a total of 2521 participants. 847 were randomly assigned to placebo, 845 to amiodarone, and 829 to ICD therapy. Design Before randomization, participants underwent electrocardiography, a 6-minute walk test, 24-hour ambulatory electrocardiography, liver and thyroid function studies, and chest radiography. Participants were required, if clinically reasonable, to receive treatment with a beta-blocker and an angiotensin-converting-enzyme inhibitor, as well as an aldosterone antagonist, aspirin, and statins, when appropriate. Participants were randomly assigned in equal proportions to receive placebo, amiodarone, or a single-chamber ICD programmed to shock-only mode. Participants assigned to amiodarone or matching placebo began therapy as outpatients immediately after randomization. Placebo and amiodarone were administered as a loading dose of 800 mg/day for one week, 400 mg/day for three weeks, and then as a daily maintenance dosage according to weight and bradycardia status. Participants assigned to ICD therapy received their device a median of three days after randomization. The goal of ICD therapy was to treat only rapid, sustained ventricular tachycardia or ventricular fibrillation. Dual-chamber or biventricular devices, or antitachycardia or rate-response pacing therapies were not permitted. The ICD was uniformly programmed to have a detection rate of 187 beats per minute or more. Antibradycardia pacing was initiated only if the intrinsic rate decreased to less than 34 beats per minute. Median follow-up was 45.5 months. The primary end point was death from any cause. Secondary outcome measures included cardiac mortality, arrhythmic mortality, morbidity, quality of life, and incremental cost-effectiveness of the interventions. Each active treatment arm was compared to the placebo drug arm. Conclusions In participants with NYHA class II or III CHF and LVEF of 35% or less, amiodarone had no favorable effect on survival, whereas single-lead, shock-only ICD therapy reduced overall mortality by 23%.

  Study phs003654

• Resuscitation Outcomes Consortium (ROC) Trauma Epidemiologic Registry (Trauma Epistry) (ROC-Trauma Epistry-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.Available Data: This dataset only includes traumatic injury participants. For ROC cardiac arrest Epistry data please see: ROC-Cardiac Epistry 1 and 2 and ROC-Cardiac Epistry 3.Objectives: To build a prospective population-based registry of participants with out-of-hospital traumatic injury responded to by Emergency Medical Services (EMS). Specific aims included: to establish whether the results of Resuscitation Outcomes Consortium (ROC) trials can be generalized to the larger population of people that experience traumatic injury; to more fully establish the burden of traumatic injury; and to examine the relationships between variation in EMS structure and process, regional and periodic factors, and participant outcomes.Background: Traumatic injury is a major public health problem generating substantial morbidity, mortality, and economic burden on society. The majority of seriously injured persons are initially evaluated and cared for by prehospital providers, however the effect of EMS systems, EMS clinical care, and EMS interventions on trauma patient outcomes is largely unknown. EMS factors such as service level, number of responding providers, use of procedures or drugs in the field, training, quality assurance/feedback, and response time intervals also vary significantly by region.The Resuscitation Outcomes Consortium (ROC) was established in 2004 to conduct clinical research in the areas of cardiopulmonary arrest and life-threatening traumatic injury with the overall goal of improving resuscitation outcomes. Previous trauma registries have generally focused primarily on hospitalized patients with limited prehospital information. Registries may also exclude trauma cases at far ends of the spectrum, such as those who die in the field or in a non-trauma center and/or patients that are treated and released. These limitations do not allow for detailed, outcome-based assessments of EMS system factors necessary to define prehospital resuscitation best practices. Therefore there was a need for standardized data collection of out-of-hospital traumatic injuries matched to hospital-based outcomes in diverse geographic locations in order to identify the independent effects of prognostic or treatment factors accounting for variations in survival. Participants: The registry included 13,830 traumatic events from 264 EMS agencies transporting to 287 acute care hospitals from the following regional centers: Birmingham, Alabama; Dallas, Texas; Iowa City, Iowa; Milwaukee, Wisconsin; Pittsburgh, Pennsylvania; Portland, Oregon; San Diego, California; Seattle/King County, Washington; Ottawa, Ontario; Toronto, Ontario; and Vancouver, British Columbia.Design: ROC Epistry collected standardized data regarding episode-specific factors, participant demographics, clinical information, pre-hospital interventions and disposition, hospital information, and participant outcome for all out-of-hospital traumatic injuries in the ROC regions. Cases were identified through review of emergency response system records including dispatch centers, EMS ground agencies, and air medical services. Out-of-hospital data were extracted from existing databases whenever possible and augmented with targeted review of EMS reports. Hospital data were abstracted directly from the hospital file in most cases. Sites submitted data using a web-based interface or batch uploads (Newgard, et al., 2008, PMID: 18482792).

  Study phs003809

• Elevated somatic mutation burdens in normal human cells due to defective DNA polymerases

  Mutation accumulation over time in normal somatic cells contributes to cancer development and is proposed as a cause of ageing. DNA polymerases POLE and POLD1 replicate DNA with high fidelity during normal cell divisions. However, in some cancers defective proofreading due to acquired mutations in the exonuclease domains of POLE or POLD1 causes markedly elevated somatic mutation burdens with distinctive mutational signatures. POLE and POLD1 exonuclease domain mutations also cause familial cancer predisposition when inherited through the germline. Here, we sequenced normal tissue DNA from individuals with germline POLE or POLD1 exonuclease domain mutations. Increased mutation burdens with characteristic mutational signatures were found to varying extents in all normal adult somatic cell types examined, during early embryogenesis and in sperm. Mutation burdens were further markedly elevated in neoplasms from these individuals. Thus human physiology is able to tolerate ubiquitously elevated mutation burdens. Indeed, with the exception of early onset cancer, individuals with germline POLE and POLD1 exonuclease domain mutations are not reported to show abnormal phenotypic features, including those of premature ageing. The results, therefore, do not support a simple model in which all features of ageing are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.

  Dataset EGAD00001006212

• Prediction of Trastuzumab Benefit in Adjuvant Breast Cancer: Gene Expression Profiling in NSABP B31

  Background National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 suggested the efficacy of adjuvant trastuzumab, even in HER2-negative breast cancer. This finding prompted us to develop a predictive model for degree of benefit from trastuzumab using archived tumor blocks from B-31. Methods Case subjects with tumor blocks were randomly divided into discovery (n = 588) and confirmation cohorts (n = 991). A predictive model was built from the discovery cohort through gene expression profiling of 462 genes with nCounter assay. A predefined cut point for the predictive model was tested in the confirmation cohort. Gene-by-treatment interaction was tested with Cox models, and correlations between variables were assessed with Spearman correlation. Principal component analysis was performed on the final set of selected genes. All statistical tests were two-sided. Results Eight predictive genes associated with HER2 (ERBB2, c17orf37, GRB7) or ER (ESR1, NAT1, GATA3, CA12, IGF1R) were selected for model building. Three-dimensional subset treatment effect pattern plot using two principal components of these genes was used to identify a subset with no benefit from trastuzumab, characterized by intermediate-level ERBB2 and high-level ESR1 mRNA expression. In the confirmation set, the predefined cut points for this model classified patients into three subsets with differential benefit from trastuzumab with hazard ratios of 1.58 (95% confidence interval [CI] = 0.67 to 3.69; P = .29; n = 100), 0.60 (95% CI = 0.41 to 0.89; P = .01; n = 449), and 0.28 (95% CI = 0.20 to 0.41; P < .001; n = 442; P interaction between the model and trastuzumab < .001). Conclusions We developed a gene expression-based predictive model for degree of benefit from trastuzumab and demostrated that HER2-negative tumors belong to the moderate benefit group, thus providing justification for testing trastuzumab in HER2-negative patients (NSABP B-47). ** Reprinted from J Natl Cancer Inst;2013;105:1782-1788 with permission from Oxford University Press.

  Study phs000826

• POPRES: Population Reference Sample

  POPRES version 1 and 2 Technological and scientific advances, stemming in large part from the Human Genome and HapMap projects, have made large-scale, genome-wide investigations feasible and cost-effective. These advances have the potential to dramatically impact drug discovery and development by identifying genetic factors that contribute to variation in disease risk as well as drug pharmacokinetics, treatment efficacy, and adverse drug reactions. In spite of the technological advancements, successful application in biomedical research would be limited without access to suitable sample collections. To facilitate exploratory genetic research, we have assembled a DNA resource from a large number of subjects participating in multiple studies throughout the world. This resource was initially genotyped using the Affymetrix 500K SNP panel. This project includes nearly 6,000 subjects of African American, East Asian, South Asian, Mexican, and European origin. POPRES version 3 The discovery and development of novel drugs is challenging and with high attrition rates. Selection of the right target and optimal indications for novel therapeutics represent key decision points in this process, and are often hampered by our limited understanding of the biology of the target in humans. Building a robust body of knowledge of variation within drug target genes has in several cases increased the probability of success for novel therapeutics. Our knowledge of variation within drug target genes and their influence on traits of medical interest is still very limited. In an effort to fill this gap, we resequenced the exons of 202 known or suspected drug target genes in over 16,000 well-phenotyped individuals. A total of 863,883 bases were targeted, including 351 kb of coding and 323 kb of untranslated exon regions. The sequenced subjects included 3,381 from two studies that were part of the Population Reference Sample (POPRES) project: CoLaus (N = 2,059) and LOLIPOP (N = 1,322). Genotyping data generated through the targeted next generation sequencing is available through the dbGaP.

  Study phs000145

• Heart Failure Network - Effectiveness of Ultrafiltration in Treating People with Acute Decompensated Heart Failure and Cardiorenal Syndrome (HFN CARRESS - BioLINCC)

  ObjectiveThe CARRESS trial examined the effectiveness of ultrafiltration compared with a strategy of diuretic-based stepped pharmacologic therapy on renal function and weight loss in patients with heart failure who have worsening renal function and persistent congestion.BackgroundAcute cardiorenal syndrome is defined as worsening renal function in patients with acute decompensated heart failure. It occurs in 25 to 33% of patients and is associated with poor outcomes. Current heart failure treatments focus on removing excess fluid buildup, however administration of intravenous diuretics may contribute to worsening renal function. Venovenous ultrafiltration is one alternative therapy that may be effective in patients with acute decompensated heart failure complicated by acute cardiorenal syndrome and persistent congestionSubjectsA total of 188 patients were randomized.DesignHospitalized subjects were randomly assigned to receive either ultrafiltration therapy or pharmacologic therapy. Ultrafiltration was performed at a fluid-removal rate of 200 ml per hour and loop diuretics were discontinued for the duration of the intervention. The addition of intravenous vasodilators or positive inotropic agents was prohibited, unless they were deemed to be necessary as rescue therapy. Patients assigned to stepped pharmacologic therapy received intravenous diuretics to manage congestion and maintain a urine output of 3 to 5 liters per day. In both groups, the assigned treatment strategy was to be continued until the signs and symptoms of congestion in the patient were reduced as much as possible. The primary end points were baseline changes in serum creatinine and weight as assessed at 96 hours after treatment assignment.ConclusionsThe use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function, and there was a similar amount of weight loss between the two groups. Ultrafiltration was associated with a higher rate of adverse events (Bart, et al., 2012, PMID: 23131078).

  Study phs003510

• The National Myelodysplastic Syndromes (MDS) Study

  Myelodysplastic syndromes (MDS) are the most common cause of adult bone marrow failure in the US and occur predominantly in people over the age of 60. Much of the morbidity and mortality for MDS is due to complications from low blood counts (e.g., infections and bleeding). MDS is caused by acquired DNA mutations that occur in a patient's blood cells as they grow older. Accumulating evidence suggests that MDS patients may traverse through a series of antecedent hematopoietic conditions defined by, i) clonal hematopoiesis (i.e., detectable somatic mutations in a person's blood cells) without low blood counts, a condition that affects up to 10% of individuals 70 years old and is termed Clonal Hematopoiesis of Indeterminate Potential (CHIP), or ii) clonal hematopoiesis with low blood counts (i.e., cytopenias) but no evidence of bone marrow dysplasia, termed Clonal Cytopenia of Undetermined Significance (CCUS). Nearly all CCUS patients will develop MDS over a ten year period, highlighting the prognostic importance of this disease. A better understanding of the genetic mutations, including non-coding and structural variants (SVs), occurring in CCUS and MDS could provide valuable insight into the natural history of MDS development. The NHLBI is conducting a longitudinal, observational study to create a standardized clinical dataset linked to a prospectively collected, consistently processed, and well-characterized biospecimen repository derived from approximately 1750 participants with suspected or newly diagnosed MDS or MDS/myeloproliferative neoplasm (MPN) overlap. These volunteers will donate biological specimens (like bone marrow and blood) and medical information, including details of their symptoms, how they perceive their quality of life, the treatments they receive, and what their doctor says about the severity of their illness over time. This information will be collected at pre-determined time points for the duration of the study. Study participants may be followed for life.

  Study phs002714

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

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

  Study phs003962

• Single cell eQTL map of T cell activation

  We isolated naive and memory CD4+ T cells from 119 healthy individuals and stimulated the cells using anti-CD3/anti-CD28 coated beads. We profiled gene expression using single cell RNA-seq (10X-Genomics 3’ v2 kit) at resting state and three time points of activation (16h, 40h and 5 days post stimulation) and mapped expression quantitative trait loci.

  Dataset EGAD00001008197

• Longitudinal profiling of the immune response to Plasmodium vivax in naive hosts by RNA-sequencing

  Plasmodium vivax offers unique challenges for control and elimination, and may prove a tougher hurdle to overcome than Plasmodium falciparum. And yet compared to P. falciparum we know very little about the innate and adaptive immune responses that need to be harnessed to reduce disease and transmission. We recently generated a blood bank of a new clonal field isolate of P. vivax (PvW1) for human challenge studies and used systems immunology tools to track the host response throughout infection and convalescence. As part of this study, RNA-sequencing was used to resolve changes in whole blood gene expression through time in 6 volunteers (7-9 time-points per volunteer). In summary, these data show that P. vivax induces two distinct transcriptional programmes in whole blood during and after infection. During infection, transcriptional profiling reveals the rapid mobilisation of an emergency myeloid response, which leads to systemic inflammation and the recruitment of all major T cell subsets into lymphoid tissues. Six days after infection, this innate response subsides and a transcriptional signature of proliferation is revealed. This most likely represents widespread activation of lymphocytes, which return to the circulation after parasite clearance - transcriptional profiling of T cells at this time-point could therefore reveal the outcomes of critical cell-cell interactions that take place within the spleen during infection. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ .

  Dataset EGAD00001006924

• Ecological Stressors, PTSD, and Drug Use in Detroit: The Detroit Neighborhood Health Study (DNHS)

  The Detroit Neighborhood Health Study (DNHS) is a prospective, representative longitudinal cohort study of predominantly African American adults living in Detroit, Michigan. The overall goal of the DNHS is to identify how genetic variation, lifetime experience of stressful and traumatic events, and features of the neighborhood environment predict psychopathology and behavior. Cohort participants were selected with a dual-frame probability design, using telephone numbers obtained from the U.S. Postal Service Delivery Sequence Files as well as a listed-assisted random-digit-dial frame. Individuals without listed landlines or telephones and individuals with only a cell phone listed were invited to participate through a postal mail effort. Participants completed a 40 minute, structured telephone interview annually between 2008-2012 to assess perceptions of participants' neighborhoods, mental and physical health status, social support, exposure to traumatic events, and alcohol and tobacco use; each participant was compensated $25USD. All survey participants were offered the opportunity to provide a specimen (venipuncture, blood spot, or saliva) for immune and inflammatory marker testing as well as genetic testing of DNA. Participants received an additional $25USD if they elected to give a sample. Informed consent was obtained at the beginning of each interview and again at specimen collection. The Institutional Review Board of the University of Michigan reviewed and approved the study protocol. The DNHS submission to dbGaP includes phenotype data from all five survey waves (n=856), all available GWAS data for participants who completed wave 4 (n=507), and methylation data for wave 1, wave 2, wave 4, and wave 5 participants (n = 456).

  Study phs000560

• Epigenetics of Cocaine and Nicotine Addiction

  This project characterizes DNA methylation and gene expression changes that occur in the human brain, specifically in neurons from the rostral striatum. Major advances from NIDA funded initiatives for noninvasive neuroimaging studies have made it possible to study neuroanatomical, neurochemical and functional changes in the human brain that contribute to the vulnerability to abuse drugs, together with the neurotoxic consequences of years of drug misuse. Animal models have been developed to explain the fundamental behavioral and biological mechanisms of addiction, including reward, tolerance and dependence. From these studies, we learned that cocaine abuse not only alters the epigenetic status of genes, but also induces particular epigenetic modifications depending on the frequency of the drug's administration. Certain genes are switched on by infrequent (short-term exposure) administration, while others are switched on only after chronic administration (addiction/dependence). Animal studies have also suggested that cocaine-seeking habits modeling chronic cocaine addiction in humans depend upon dopamine-dependent serial connectivity linking the ventral (nucleus accumbens) with the dorsal striatum (caudate nucleus). The primary goal of this study is to identify DNA methylation and gene expression changes that occur in the transition from recreational cocaine use to cocaine addiction. High throughput sequencing studies were designed to investigate unique postmortem human brain specimens from individuals that met criteria for cocaine dependence, as compared to unaffected age-matched controls. Brain biospecimens were available from the University of Miami Brain Endowment BankTM, from a collection of phenotypically well-characterized postmortem tissues sampled from chronic cocaine abusers that came to autopsy. This biobank of postmortem brain specimens and annotated genomic data serve as a research resource to support NIDA's scientific mission.

  Study phs001377

• Genomic Studies in Charcot-Marie-Tooth Disease

  The various forms of Charcot-Marie-Tooth disease (CMT) comprise a genetically heterogeneous set of peripheral neuropathies. Currently, >90 different CMT genes have been identified; yet, for the axonal CMT2 subtype these genes explain only 30-40% of the genetic effect. In particular, the application of exome sequencing has led to an unprecedented pace in identifying about half of those genes in the past five years. We have been at the forefront of this development with 22+ published new gene identifications in the past seven years. This success was only possible through broad national and international collaborations, data sharing, and the development of advanced analysis tools and methods. We also learned that despite an accumulation of exome sequencing data, over 50% of axonal CMT patients remain undiagnosed, suggesting even more genes are involved; additionally, our preliminary data also support the existence of non-coding variations as Mendelian allele contributors. In this study, we will continue our highly impactful work in CMT family recruitment, exome sequencing and traditional gene identification. In addition, we will expand the genetic studies to whole genome sequencing with a focus on families already explored unsuccessfully in whole exome studies. We further plan to perform the first large rare variant burden analysis in the rare disorder CMT2. This is only possible through the exceptional clinical resources we have built over the past decade. Finally, with many CMT genes available, we will perform statistical network analyses on a CMT-ome to identify gene modules and pathways that will be the starting point of polypharmacology, and provide insight into pathophysiology of peripheral nerve degeneration. All data will be available in real-time to an existing network of CMT investigators worldwide, and deposited in dbGaP annually.

  Study phs003389

• Sudden Death in the Young Case Registry

  Knowledge gaps persist about the incidence of and risk factors for sudden death in the young (SDY). The SDY Case Registry is a collaborative effort between the National Institutes of Health, the Centers for Disease Control and Prevention, and the Michigan Public Health Institute. Its goals are to: (1) describe the incidence of SDY in the United States by using population-based surveillance: (2) compile data from SDY cases to create a resource of information and DNA samples for research; (3) encourage standardized approaches to investigation, autopsy, and categorization of SDY cases; (4) develop partnerships between local, state, and federal stakeholders toward a common goal of understanding and preventing SDY; and (5) support families who have lost loved ones to SDY by providing resources on bereavement and medical evaluation of surviving family members. Built on existing Child Death Review programs and as an expansion of the Sudden Unexpected Infant Death Case Registry, the SDY Case Registry achieves its goals by identifying SDY cases, providing guidance to medical examiners/coroners in conducting comprehensive autopsies, evaluating cases through child death review and an advanced review by clinical specialists, and classifying cases according to a standardized algorithm. The SDY Case Registry also includes a process to obtain informed consent from next-of-kin to save DNA for research, banking, and, in some cases, diagnostic genetic testing. The SDY Case Registry will provide valuable incidence data and will enhance understanding of the characteristics of SDY cases to inform the development of targeted prevention efforts. For cases where informed consent has been obtained for research genomic sequencing has been performed. On these cases genomic data, phenotype information and on a limited number of cases redacted autopsy reports will be available through dbGaP.

  Study phs003221

• Hispanic Community Health Study /Study of Latinos (HCHS/SOL)

  The Hispanic Community Health Study / Study of Latinos (HCHS/SOL) is a multi-center epidemiologic study in Hispanic/Latino populations to determine the role of acculturation in the prevalence and development of disease, and to identify risk factors playing a protective or harmful role in Hispanics/Latinos. The study is sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and six other institutes, centers, and offices of the National Institutes of Health (NIH). The goals of the HCHS/SOL include studying the prevalence and development of disease in Hispanics/Latinos, including the role of acculturation, and identifying disease risk factors that play protective or harmful roles in Hispanics/Latinos. A total of 16,415 persons of Cuban, Dominican, Mexican, Puerto Rican, Central American, and South American backgrounds were recruited through four Field Centers affiliated with San Diego State University, Northwestern University in Chicago, Albert Einstein College of Medicine in the Bronx area of New York, and the University of Miami. Seven additional academic centers serve as scientific and logistical support centers. Study participants aged 18-74 years took part in an extensive clinic exam and assessments to ascertain socio-demographic, cultural, environmental and biomedical characteristics. Annual follow-up interviews are conducted to determine a range of health outcomes. The HCHS SOL Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" section of this top-level study page phs000810 HCHS SOL Cohort. phs000555 PAGE CALiCo SOL phs000880 HCHS/SOL Omics in Latinos (Ola)

  Study phs000810

• Genetic Neuroscience: How Human Genes and Alleles Shape Neuronal Phenotypes

  The goal of this collaborative, interdisciplinary project is to develop powerful, generalizable approaches for discovering how risk variants for psychiatric disorders shape neurobiological processes at multiple levels of analysis, and to identify the processes whose dysregulation underlies disease.Induced pluripotent stem cells (iPSCs) were used towards the development of these new experimental and inferential systems bridging gaps between human genetics and experimental biology. The largest publicly available collection of iPSCs (2607 lines) has been generated from 2184 donors by the California Institute for Regenerative Medicine (CIRM). To expand our donor collection, an additional 44 iPSC donors from the McLean_Levy cohort were identified. We wish to share the available SNP data for 2167 CIRM lines and whole genome sequence data generated at the Broad Institute for 473 of the CIRM and 44 McLean_Levy iPSC donors. These data can be used to identify (for experiments) lines with specific genotypes of interest and lines from donors with high or low polygenic risk scores for phenotypes of interest. The data can also be used to identify acquired mutations in the iPSC lines. The CIRM iPSC lines are available through Fujifilm Cellular Dynamics iPSC Repository (https://www.fujifilmcdi.com/cirm-ipsc-products/). The McLean_Levy lines are available through the NIMH Repository & Genomics Resource (https://www.nimhgenetics.org/).Additional project data registered with the study includes data from an iPSC line derived from an SMA patient (n=1), as well as single-cell RNA sequence data and supplemental processed genomic datasets in support of project publications.Molecular DatasetsSingle-cell RNA-seq: 10X Genomics, Illumina NovaSeqSupplemental "cell village" pooled genomic sequence data: Illumina NextSeqWhole Genome Genotyping: Infinium Global Screening Array-24 Kit, Illumina HumanCore chipWhole Genome Sequencing: Illumina NovaSeq

  Study phs002032

• High Frequency Ventilation in Premature Infants (HIFI-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: To evaluate the hypothesis that high frequency oscillatory ventilation in preterm infants would reduce the incidence of mortality and pulmonary complications compared to conventional mechanical ventilation.Background: With the introduction of mechanical ventilation in preterm infants, mortality and morbidity significantly improved but remained high. The improvement in survival that accompanied the use of mechanical ventilation also brought about an increase in the incidence of pulmonary complications. The principal complication occurs in the form of bronchopulmonary dysplasia. Barotrauma and oxygen toxicity are considered to be in the pathogenesis for this disorder. Considerable interest in high frequency ventilation for preterm infants was generated when animal studies indicated high frequency ventilation to be effective in promoting gas exchange without apparent adverse effects. High Frequency Ventilation (HFV) delivers small tidal volumes at high frequencies of 4 to 15 Hz, and animal studies had indicated that HFV was associated with effective gas exchange, less barotrauma, and lower mean airway pressure. However, the efficacy and safety of HFV in preterm infants had not been studied. The HIFI Planning Phase was initiated in August 1984, and recruitment and intervention began in February, 1986. Follow-up studies continued thru September, 1988.Participants: A total of 673 infants were enrolled.Conclusions: Bronchopulmonary dysplasia incidence was similar in the two groups as was mortality and the need for ventilatory support during the first 28 days. There was a significantly greater rate of pneumoperitoneum of pulmonary origin in the high frequency group as was a greater incidence rate of intracranial hemorrhage. (HIFI Study Group, 1989, PMID: 2643039)

  Study phs004032

• Convergent evolution towards CD38 biallelic loss is a recurrent mechanism of resistance to anti-CD38 antibodies in multiple myeloma.

  Monoclonal antibodies directed against CD38 are a therapeutic mainstay in multiple myeloma (MM). While they have contributed to improved outcomes, most patients will still experience disease relapse. Despite their ubiquity, little is known about tumor-intrinsic mechanisms of resistance to these drugs. Antigen escape, whereby tumor cells alter expression of cell surface immunotherapy targets, has been proposed as a potential avenue, and has been seen with other immunotherapies in MM. Yet, it is unknown whether MM cells can develop permanent resistance to anti-CD38 antibodies by acquiring genomic events leading to biallelic disruption of the CD38 gene locus. Here, by using whole genome and whole exome sequencing data from 701 newly diagnosed patients, 72 patients at relapse with naivety to anti-CD38 antibodies, and 52 patients collected at relapse following anti-CD38 antibodies, we report biallelic inactivation of CD38 as a recurrent mechanism of resistance in 6% of patients, often via convergent evolution where distinct subclones are advantaged towards the same selective endpoint within the same patient. Monoallelic loss of the CD38 locus was seen in another 14% post-CD38-directed therapy. Three of the cases with biallelic events on CD38 presented with missense mutations and retained CD38 expression. Functional work demonstrated that two of these mutations decreased binding affinity and antibody-dependent cellular cytotoxicity of commercial antibodies Daratumumab and Isatuximab. However, the third mutation (R140G) provided relative resistance only towards one commercial product. Given that patients are often rechallenged with CD38 antibodies following disease progression, these data support the need for next generation sequencing to guide treatment selection.

  Study EGAS50000000709

• RNAseq: Acquired non-permissive bone marrow microenvironment impairs hematopoietic stem cell proliferation and maintenance and B-cell development post-HSCT

  Defects in B-cell reconstitution upon hematopoietic stem-cell (HSC) transplantation (HSCT) are a common observation, yet the mechanism remains unexplained. The bone marrow (BM) stroma, including mesenchymal stromal cells (MSCs), guides HSC maintenance and B-lymphopoiesis by secreting crucial cytokines. We report acquired, permanent, selective and complete B-cell deficiency in the context of full donor-chimerism in a patient with X-linked lymphoproliferative disease and aimed to identify the contribution of the BM-microenvironment in disrupted B-cell reconstitution post-HSCT. We studied longitudinal BM samples from the patient and his identical twin, both of whom underwent HSCT with the same donor with opposite outcomes in B-cell reconstitution. In the index patient BM, we observed progressive loss of proliferation of HSCs and a selective block at the pre-BI cell stage. In vitro modeling studies showed limited survival of patient-HSCs and a relative accumulation of pre-B cells. Patient-derived MSCs failed to support survival and proliferation of HSCs and B-cell development of healthy-HSCs which was correlated with reduced CXCL12 levels. Using bulk RNA-sequencing of MSCs and in vitro functional studies, we showed global changes in the patients’ MSCs and a progressive loss of CXCL12 expression. Indeed, survival of patients HSCs improved supplementing in vitro development culture with CXCL12, suggesting a contribution of defective CXCL12 signaling to the phenotype. In summary, our data show that an acquired defect in the BM-stromal microenvironment and exhaustion of HSCs and committed progenitors may cause a permanent non-permissive state for normal B-cell development.

  Study EGAS50000001437

• ATAC-seq: Acquired non-permissive bone marrow microenvironment impairs hematopoietic stem cell proliferation and maintenance and B-cell development post-HSCT

  Defects in B-cell reconstitution upon hematopoietic stem-cell (HSC) transplantation (HSCT) are a common observation, yet the mechanism remains unexplained. The bone marrow (BM) stroma, including mesenchymal stromal cells (MSCs), guides HSC maintenance and B-lymphopoiesis by secreting crucial cytokines. We report acquired, permanent, selective and complete B-cell deficiency in the context of full donor-chimerism in a patient with X-linked lymphoproliferative disease and aimed to identify the contribution of the BM-microenvironment in disrupted B-cell reconstitution post-HSCT. We studied longitudinal BM samples from the patient and his identical twin, both of whom underwent HSCT with the same donor with opposite outcomes in B-cell reconstitution. In the index patient BM, we observed progressive loss of proliferation of HSCs and a selective block at the pre-BI cell stage. In vitro modeling studies showed limited survival of patient-HSCs and a relative accumulation of pre-B cells. Patient-derived MSCs failed to support survival and proliferation of HSCs and B-cell development of healthy-HSCs which was correlated with reduced CXCL12 levels. Using bulk RNA-sequencing of MSCs and in vitro functional studies, we showed global changes in the patients’ MSCs and a progressive loss of CXCL12 expression. Indeed, survival of patients HSCs improved supplementing in vitro development culture with CXCL12, suggesting a contribution of defective CXCL12 signaling to the phenotype. In summary, our data show that an acquired defect in the BM-stromal microenvironment and exhaustion of HSCs and committed progenitors may cause a permanent non-permissive state for normal B-cell development.

  Study EGAS50000001438

• Repotrectinib in NTRK fusion–positive advanced solid tumors: a phase 1/2 trial

  Early-generation TRK tyrosine kinase inhibitors (TKIs) approved for treating NTRK fusion–positive (NTRK+) solid tumors provide clinical benefit; however, resistance emerges. Repotrectinib is a next-generation ROS1/TRK TKI with a compact macrocyclic structure designed to improve durability of response. TRIDENT-1 is a registrational phase 1/2 trial assessing repotrectinib, a next-generation ROS1/TRK TKI, in adults with advanced solid tumors, including NTRK+ disease. The primary endpoint was confirmed objective response; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival and safety. Median follow-up ranged between 21.3 months and 25.7 months. In the TKI-naive cohort (n = 51; 95% confidence interval (CI)), the response rate was 59% (44–72); the median DOR was not estimable (NE); and the median PFS was 30.3 months (9.0–NE). In the TKI-pretreated cohort (n = 69; 95% CI), the response rate was 48% (36–60); the median DOR was 9.8 months (7.4–13.0); and the median PFS was 7.4 months (3.9–9.7). Of 30 TKI-pretreated patients with NTRK solvent front mutations, 16 had a response (53%; 95% CI: 34–72). Intracranial responses were observed in two of three TKI-naive patients and in four of six TKI-pretreated patients with measurable intracranial disease at baseline. Among all treated patients (n = 565), the most common any-grade treatment-related adverse event (TRAE) was dizziness (57%); most TRAEs were low grade; and 4% discontinued repotrectinib due to a TRAE. Overall, repotrectinib demonstrated durable systemic and intracranial responses with generally low-grade adverse events in patients with NTRK+ solid tumors, including those with previous TRK TKI treatment and solvent front mutations. These results support the use repotrectinib to treat patients with NTRK+ solid tumors. ClinicalTrials.gov identifier: NCT03093116 .

  Study EGAS50000001572

• Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma

  Background:Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples. Methods:Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed. Results:Sequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment were observed and led to a switch from a hot to a cold immune profile in three patients. Conclusions:This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support

  Study EGAS00001005328

• Altered oligodendrocyte heterogeneity in Multiple sclerosis revealed by single nuclei RNA sequencing

  This study is currently hosted by the European Nucleotide Archive. To access the data contained within the Study please follow the link below: https://www.ebi.ac.uk/ena/browser/view/PRJEB39323 Oligodendrocyte (OL) pathology is increasingly implicated in neurodegenerative diseases, as they are involved in metabolic support of axons and functional cross-talk with other brain cells. Rodent OLs are heterogeneous, with developmental and biological differences, but the extent of heterogeneity in the normal human brain and its contribution to any changes to disease remains unknown. Here we performed single nuclei RNA-sequencing (snRNA-seq) from white matter (WM) areas of post mortem human brain both in control (Ctr) and multiple sclerosis (MS) patients. We identified several sub-clusters of oligodendroglia in the Ctr human WM, some similar to those in mouse, and defined new markers for these cell states. Strikingly, some of these sub-clusters were under-represented in MS tissue, while others were more prevalent than in controls. We found a lack of OL precursor cells (OPCs) and an OL subcluster in an intermediate stage of differentiation in MS lesions and in normal appearing white matter (NAWM), suggesting either depletion by the disease or by a regenerative response. The differences in mature OL sub-clusters indicate different functional states of OLs in MS tissue and, as this is similar in NAWM to lesions, that MS is a more diffuse brain disease than the focal demyelinating lesions suggest. We were also able to identify new putative markers of different MS lesion subtypes. Our findings of an altered heterogeneity of oligodendroglia in MS may have an important contribution to our understanding of disease progression and may alter therapeutic approaches to MS.

  Study EGAS00001003412

• Targeting FGFR1 for treatment of soft-tissue sarcoma (H021)

  Purpose: Altered FGFR1 signaling has emerged as therapeutic target in various epithelial malignancies. In contrast, the role of FGFR1 in soft-tissue sarcoma (STS) has not been established. Prompted by the detection and subsequent therapeutic inhibition of amplified FGFR1 in a patient with metastatic leiomyosarcoma, we investigated the oncogenic properties and potential as drug target of FGFR1 in STS.Experimental Design: The frequency of FGFR1 amplification and overexpression, as assessed by fluorescence in situ hybridization, microarray-based comparative genomic hybridization and mRNA expression profiling, SNP array profiling, and RNA sequencing, was determined in three independent patient cohorts. The sensitivity of STS cell lines with or without FGFR1 alterations to genetic and pharmacologic FGFR1 inhibition and the signaling pathways engaged by FGFR1 were investigated using short-term viability assays, long-term colony formation assays, and biochemical analysis.Results: Increased FGFR1 copy number was detected in 74 of 190 (38.9%; Cohort 1), 13 of 79 (16.5%; Cohort 2), and 80 of 254 (31.5%; Cohort 3) patients. FGFR1 overexpression occurred in 16 of 79 (20.2%, Cohort 2) and 39 of 254 (15.4%; Cohort 3) patients. Targeting of FGFR1 by short hairpin RNA-mediated knockdown and different small-molecule inhibitors (PD173074, AZD4547, BGJ398) revealed that the requirement for FGFR1 signaling in STS cells is primarily dictated by FGFR1 expression levels, and identified the MAPK-ERK1/2 axis as critical FGFR1 effector pathway.Conclusion: These data identify FGFR1 as driver gene in multiple STS subtypes and support FGFR1 inhibition, guided by patient selection according to FGFR1 expression and monitoring of MAPK-ERK1/2 signaling, as therapeutic option in this challenging group of diseases.H021

  Study EGAS00001001844

• Genetics and therapeutic responses to TIL therapy of pancreatic cancer PDX models

  Pancreatic cancer is the 7th leading cause of cancer-related deaths worldwide. Checkpoint immunotherapy has not yet showed encouraging results in pancreatic cancer possibly owing to a poor immunogenicity and/or an immune suppressive microenvironment. The aim of this study was to develop patient-derived xenografts (PDX) models and to assess if autologous tumor-infiltrating lymphocytes (TILs) would have anti-tumoral activity in pancreatic cancer. Tumor biopsies from 29 patients were subcutaneously transplanted into NOG mice. Tumor growths were confirmed in 11 out of 29 transplantations. The PDX tumors histologically resembled their original biopsies, but since stromal cells in the PDX model tumors were from mouse, their gene expression differed from the original biopsies. Immune checkpoint ligands other than PD-L1 were expressed in pancreatic cancers but PD-L1 was rarely expressed. One of the three tumors that did express PD-L1 was an adenosquamous cancer and another had a mismatch repair deficiency. TILs were expanded from six tumors and were injected into NOG or human interleukin-2 transgenic-NOG (hIL2-NOG) mice carrying PDX tumors. Regression of tumors could be verified in hIL2-NOG mice in 3 of the 6 PDX models treated with autologous TILs, including the adenosquamous PDX model. In conclusion, PDX models of pancreatic cancer can be used to learn more about tumor characteristics and biomarkers, and to evaluate responses to ACT and combination therapies. The major benefit of the model is that modifications of T cells can be tested in an autologous humanized mouse model to gain preclinical data to support the initiation of a clinical trial.

  Study EGAS00001005596

• Monocyte and macrophage lipid accumulation results in downregulated type-I interferon responses

  Macrophages are critical components of atherosclerotic lesions and their pro- and anti-inflammatory responses influence atherogenesis. Type-I interferons (IFNs) are cytokines that play an essential role in antiviral responses and inflammatory activation and have been shown to promote atherosclerosis. Although the impact of type-I IFNs on macrophage foam cell formation is well-documented, the effect of lipid accumulation in monocytes and macrophages on type-I IFN responses remains unknown. Here we examined IFN stimulated (ISG) and non-ISG inflammatory gene expression in mouse and human macrophages that were loaded with acetylated LDL (acLDL), as a model for foam cell formation. We found that acLDL loading in mouse and human macrophages specifically suppressed expression of ISGs and IFN-β secretion, but not other pro-inflammatory genes. The downregulation of ISGs could be rescued by exogenous IFN-β supplementation. Activation of the cholesterol-sensing nuclear liver X receptor (LXR) recapitulated the cholesterol-initiated type-I IFN suppression. Additional analyses of murine in vitro and in vivo generated foam cells confirmed the suppressed IFN signalling pathways and suggest that this phenotype is mediated via downregulation of interferon regulatory factor binding at gene promoters. Finally, RNA-seq analysis of monocytes of familial hypercholesterolemia (FH) patients also showed type-I IFN suppression which was restored by lipid-lowering therapy and not present in monocytes of healthy donors. Taken together, we define type-I IFN suppression as an athero-protective characteristic of foamy macrophages. These data provide new insights into the mechanisms that control inflammatory responses in hyperlipidaemic settings and can support future therapeutic approaches focusing on reprogramming of macrophages to reduce atherosclerotic plaque progression and improve stability.

  Study EGAS00001005955

• Germline variants in patients with rare cancers and their implications for precision cancer medicine: experiences from the Multicenter MASTER Trial by the German Cancer Consortium (HIPO_021)

  The era of precision oncology entails an increasing amount of molecular data from tumor sequencing in research and diagnostics. In this setting, germline variant analysis may add clinical benefits for patients and family members. In this study, we evaluated germline variants from genome/exome matched tumor-blood sequencing in 1.485 advanced cancer patients within a prospective observational study carried out by the German Cancer Consortium. Included patients had cancers of rare entities (79.2%) or were under the age of 51 at first diagnosis (76.6%). Ten percent of the patients harbored pathogenic germline variants in 35 tumor predisposition genes with autosomal-dominant inheritance such as BRCA1, BRCA2, TP53, RB1, CHEK2, ATM, PALB2, SDHB etc., while 4.6% of the patients were carriers of pathogenic germline variants in 18 genes with autosomal-recessive inheritance of tumor predisposition. Based on pathogenic germline variants, 14% of the patients received genetic counselling recommendations in the molecular tumor board report. Forty five percent of pathogenic germline variants supported a molecular treatment recommendation, which was implemented for 28 patients. Furthermore, we compared our approach and results to previous studies, broadening the insight into pan cancer germline findings but also revealing differences between studies on various levels, such as cohort demographics, tumor entities, gene nominations, variant detection and variant interpretation. Our data support the importance of germline variant interpretation in precision oncology studies for patients and their families, if applicable. However, guidelines for evaluation and reporting of germline variants in the context of genetic tumor profiling need to be established and further research on the relevance of germline mutations as biomarkers for treatment recommendations is needed.

  Study EGAS00001005537

• Genetic heritage of the Baphuthi highlights an over-ethnicised notion of 'Bushman' in the Maloti-Drakensberg, southern Africa

  Using contemporary people as proxies for ancient communities is a contentious but necessary practice in anthropology. In southern Africa, the distinction between the Cape KhoeSan and eastern KhoeSan remains unclear as ethnicity labels have been changed through time and most communities were decimated if not extirpated. The eastern KhoeSan may have had genetic distinctions from neighbouring communities who speak Bantu languages and KhoeSan further away, alternatively the identity may not have been tied to any notion of biology, instead denoting communities with a nomadic 'lifeway' distinct from African agro-pastoralism. The Baphuthi of the 1800s in the Maloti-Drakensberg, southern Africa had a substantial KhoeSan constituency and a lifeway of nomadism, cattle raiding, and horticulture. Baphuthi heritage could provide insights into the history of the eastern KhoeSan. We examine genetic affinities of 23 Baphuthi to discern whether the narrative of KhoeSan descent reflects distinct genetic ancestry. Genome-wide SNP data (Illumina GSA) were merged with 52 global populations, for 160K SNPs. Genetic analyses show no support for a unique eastern KhoeSan ancestry distinct from other KhoeSan or southern Bantu-speakers. The Baphuthi have strong affinities with early-arriving southern Bantu-speaking (Nguni) communities, as the later-arriving non-Nguni show strong evidence of recent African admixture possibly related to Late-Iron Age migrations. The references to communities as 'San',and 'Bushman' in historic literature has often been misconstrued as notions of ethnic/biological distinctions. The terms may have reflected ambiguous references to non-sedentary polities instead, as seems to be the case for the eastern ‘Bushman’ heritage of the Baphuthi.

  Study EGAS00001007080

• IL7-receptor expression is frequent in T-cell acute lymphoblastic leukemia and predicts sensitivity to JAK-inhibition

  T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a dismal prognosis related to refractory/relapsing diseases, raising the need for new targeted-therapies. Activating mutations of the IL7-receptor pathway genes (IL7Rp) play a proven leukemia-supportive role in T-ALL. JAK-inhibitors such as ruxolitinib have recently demonstrated preclinical efficacy. However, prediction markers for sensitivity to JAK-inhibitors are still lacking. Herein, we show that IL7R (CD127) expression is more frequent (~70%) than IL7Rp-mutations in T-ALL (~30%). We compared the so-called non-expressers (no IL7R-expression/IL7Rp-mutation), expressers (IL7R-expression without IL7Rp-mutation) and mutants (IL7Rp-mutations). Integrative multi-omics analysis outlined IL7R-deregulation in virtually all T-ALL subtypes, at the epigenetic-level in non-expressers, genetic-level in mutants, and post-transcriptional level in expressers. Ex-vivo data using primary-derived xenografts support that IL7Rp is functional whenever the IL7R is expressed, regardless of the IL7Rp mutational status. Consequently, ruxolitinib impaired T-ALL survival in both expressers and mutants. Interestingly, we show that expressers displayed ectopic IL7R-expression and IL7Rp-addiction conferring a deeper sensitivity to ruxolitinib. Conversely, mutants were more sensitive to venetoclax than expressers. Overall, combination of ruxolitinib and venetoclax resulted in synergistic effects in both groups. We illustrate the clinical relevance of this association by reporting achievement of complete remission in two patients with refractory/relapsed-T-ALL. This provides proof of concept for translation of this strategy into clinics as bridge to transplant. Altogether, IL7R-expression can be used as a biomarker for sensitivity to JAK-inhibition, thereby expanding the fraction of T-ALL patients eligible to ruxolitinib up to nearly ~70% of T-ALL.

  Study EGAS00001007144

• Smoking-dependent expression alterations in nasal epithelium reveal immune impairment linked to germline variation and lung cancer risk.

  Lung cancer is the leading cause of cancer-related death in the world. In contrast to many other cancers, a direct connection to lifestyle risk in the form of cigarette smoke has long been established. More than 50% of all smoking-related lung cancers occur in former smokers, often many years after smoking cessation. Despite extensive research, the molecular processes for persistent lung cancer risk are unclear. CT screening of current and former smokers has been shown to reduce lung cancer mortality by up to 26%. To examine whether clinical risk stratification can be improved upon by the addition of genetic data, and to explore the mechanisms of the persisting risk in former smokers, we have analyzed transcriptomic data from accessible airway tissues of 487 subjects. We developed a model to assess smoking associated gene expression changes and their reversibility after smoking is stopped, in both healthy subjects and clinic patients. We find persistent smoking associated immune alterations to be a hallmark of the clinic patients. Integrating previous GWAS data using a transcriptional network approach, we demonstrate that the same immune and interferon related pathways are strongly enriched for genes linked to known genetic risk factors, demonstrating a causal relationship between immune alteration and lung cancer risk. Finally, we used accessible airway transcriptomic data to derive a non-invasive lung cancer risk classifier. Our results provide initial evidence for germline-mediated personalised smoke injury response and risk in the general population, with potential implications for managing long-term lung cancer incidence and mortality.

  Dac EGAC50000000169

• High-depth whole genome sequencing of 26 premalignant breast lesions

  Ductal carcinoma in situ (DCIS) is a non-obligate precursor lesion of breast cancer, representing 20-25% of newly diagnosed breast cancer lesions. It is currently not possible to predict which DCIS patients will progress to invasive breast cancer. The samples deposited here are part of a larger study using high-depth whole-genome sequencing (WGS) to investigate the somatic mutation genomic landscape of DCIS. Comprehensive evaluation of DCIS genomes aims to uncover biological insights into breast cancer progression and potential opportunities to stratify DCIS patients for personalised treatment options or active surveillance. Due to specific restrictions imposed by the ethical approval at sample collection, the use of the germline data is restricted to filtering of somatic mutation calls only and cannot be used outside this purpose.

  Study EGAS50000001559

• scRNA-seq of total bone marrow and T cells from multiple myeloma long-term survivors

  scRNA This dataset contains 50 scRNA-seq samples from bone marrow aspirates of 11 multiple myeloma patients experiencing long-term survival and 3 healthy donors. For each donor, total bone marrow and CD3+ T cells were sequenced. For multiple myeloma patients, paired samples were collected at initial diagnosis and between 7-17 years after first-line therapy. Bone marrow mononuclear cells were isolated by Ficoll density gradient centrifugation. For sorting of total bone marrow cells singlet, live cells were gated and sorted, for sorting of T cells CD45+, CD3+ cells were gated and sorted on either FACSAria Fusion or FACSAria II. Single-cell RNA sequencing were generated using 10x Genomics single-cell RNAseq technology (Chromium Single Cell 3’ Solution v2) according to the manufacturer’s protocol and sequenced on an Illumina HiSeq4000 (paired end, 26 and 74 bp). Bulk RNA Singlet, live CD3+CD4- CXCR3+CD8+ and CD3+CD4- CXCR3-CD8+ cells were sorted from 7 bone marrow and 3 peripheral blood samples of 7 multiple myeloma patients using a FACSAria Fusion machine. Bulk-RNA sequencing libraries were generated using the SMART Seq Stranded Total RNA-Seq kit (Takara) and sequenced using the Illumina NovaSeq 6000 platform (2 x 100 bp).

  Dataset EGAD00001010025

• Influence of the Microbiome on Epigenetic Mechanisms in IBD

  Live CD4 T cells were sorted from inflamed and non-inflamed tissue samples of IBD patients or from healthy and IBD blood samples. ATAC-Seq libraries were generated from live CD4 T cells sorted from i) inflamed and non-inflamed tissue samples, ii) healthy and IBD blood samples, or from iii) CD4 T cell subsets polarised from healthy blood samples. After isolating crude nuclei, live CD4+ T cells were treated with Tagment DNA buffer and Tagment DNA Enzyme (Nextera DNA Library Prep Kit, Illumina), and then the DNA was purified by MinElute PCR Purification Kit (Qiagen). Transposed DNA fragments were amplified using specific adapters followed by purification with MinElute PCR Purification Kit (Qiagen). Fragments from 240-360pb were selected in the PippinHT system (Sage Science). The quality of the library and its DNA concentration were assessed by Bioanalyzer instruments (Agilent Technologies) and ultimately submitted for sequencing using Illumina HiSeq 2500 sequencer, V4 chemistry. On the other hand, single cell RNA-Seq libraries were generated exclusively from inflamed and non-inflamed tissue samples of Crohn’s disease patients. Briefly, live CD4 T cells were captured and encapsulated before cDNA amplification using the 10X Genomics Chromium Platform. Samples were prepared as outlined by 10x genomics Single Cell 3’ Reagent Kits v2 user guide. Samples were sequenced on a HiSeq 2500 with the following run parameters: Read 1 – 26 cycles, read 2 – 98 cycles, index 1 – 8 cycles.

  Dataset EGAD00001011066

• Genome-Wide Association Studies of Prematurity and Its Complications

  Preterm labor resulting in the delivery of a premature child is a complex problem with an enormous impact on individuals, families and society. An estimated 500,000 children are born prematurely in the U.S. each year, and 5 million worldwide die annually of prematurity and its complications. Prematurity is also the single largest contributor to disability-adjusted life years, a measure of the lifetime impact of a disease. Despite the importance of the problem and its disproportionate occurrence in poor and minority populations, its underlying etiology (or etiologies) remains unknown; the single best predictor for preterm delivery is a previous preterm birth. The largest single cause of prematurity is spontaneous preterm labor, and suspected triggers for this include infection, stress, poor nutrition and genetic factors. Family and twin studies provide strong evidence that genetic factors underlie about 40% of the risk for prematurity. A major challenge in studying genetic factors in prematurity is maternal/uterine factors, fetal/placental factors, or both may influence risk. Thus, any approach to studying preterm birth should account for both infant and maternal risk, environmental covariates and interactions. The Danish National Birth Cohort (DNBC) is a well-established, prospective cohort that enrolled women early in pregnancy, prior to any adverse pregnancy outcomes, to minimize bias in data collection and sampling. See details at: http://www.ssi.dk/English. The DNBC followed over 100,000 pregnancies beginning in the first trimester and has extensive biological material and epidemiologic data on health outcomes in both mother and child. The current study posted on dbGaP contains data from a genome-wide case/control study using approximately 1,000 preterm mother-child pairs from the DNBC most with spontaneous onset of labor or preterm premature rupture of membranes (PPROM), along with 1,000 control pairs where the child was born at ~40 weeks' gestation. After data cleaning some small changes in case/control status and other variables resulted in minor changes in numbers of cases or controls in certain categories. Environmental variables are being used as covariates in the analysis. To replicate positive findings, we are using additional mother-child pairs from the DNBC and from the general Danish population, as well as 2200 samples coming primarily from an African-American population known to have high rates of preterm labor and delivery. This group includes over 1000 mostly very low birthweight infants, over 500 infant term controls, 326 term mother/baby pairs and 180 preterm mother/baby pairs. The data from these additional cohorts will be available in separate dbGaP postings. The study is expected to yield a better understanding of the biology of parturition, identify common genetic factors that play a role in preterm birth and its complications and suggest environmental modifications that can prolong gestation, with the goal of improving both neonatal and adult outcomes. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to prematurity and its complications through large-scale genome-wide association studies of a well-characterized cohort of Danish mothers and babies. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000103

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

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

  Study phs000430

• Whole Genome Sequencing of a Triple Negative Breast Cancer Patient: Matched Primary Tumor, Normal, Metastasis and Xenograft samples

  Breast Cancer Subject Participant ID 700064 (Source Sample names: 6888 and 206). We used massively parallel DNA sequencing technologies to screen entire genomes, in an unbiased manner, for genetic changes associated with tumor growth and metastasis. We describe the complete genome sequence analysis of four DNA samples from a 44-year old African-American patient with basal-like breast cancer: peripheral blood, the primary tumor, a brain metastasis that developed within a year of initial therapy, and a first-passage xenograft derived from the primary tumor. A total of 50 validated mutations were discovered within coding, RNA, or splice site sequences. Of these, 20 mutations were abundantly present in all three tumors, including mutations in CSMD1 and JAK2. These two genes subsequently were found to be mutated in other breast tumors. The metastasis contained two de novo mutations not present in the primary tumor, and was significantly enriched for 20 shared mutations, suggesting that they may be involved in the metastatic process. The xenograft contained no unique coding, RNA, or splice site mutations and retained all primary tumor mutations, albeit at different frequencies. However, a significant increase in copy number alterations was observed in the xenograft as compared to the primary tumor. We validated 28 large deletions and six inversions, as well as seven translocations in at least one of the three tumor samples. Among them, a 26 kb deletion in MECR was solely identified, assembled, and validated in the brain metastasis and two overlapping large deletions on chromosome 5 encompassing CTNNA1, a potential tumor suppressor gene, were identified in all three tumors. The differential mutation frequencies and structural variation patterns between primary and metastatic tumors suggest that metastatic tumors may arise from minor subpopulations of cells within the primary. Namely, the metastatic and xenografting processes apparently select for cells harboring a distinct subset of the primary tumor mutation repertoire.

  Study phs000245

• Genetic analysis of HLA and immune escape genes in Diffuse Large B-cell Lymphoma

  Fifty percent of diffuse large B-cell lymphoma (DLBCL) cases lack cell-surface expression of the class-I major histocompatibility complex (MHC-I), thereby escaping immune recognition by cytotoxic T cells. In order to comprehensively identify the mechanisms involved in MHC-I loss, we first performed immunophenotypic analysis of both MHC class-I and -II in 657 cases across the spectrum of B-NHL, revealing that loss of MHC-I, but not MHC-II, is preferentially restricted to DLBCL. We then used whole exome and targeted deep-sequencing to examine genes involved in MHC-I expression in 74 DLBCL samples representative of MHC-I positive and negative cases. We show here that somatic biallelic or monoallelic inactivation of B2M and/or HLA-I is present in 80.9% (34/42) of MHC-I negative tumors. Furthermore, 68.8% (22/32) of MHC-I positive DLBCLs also harbored monoallelic HLA-I genetic alterations (MHC-I positivemono) that lead to allelic imbalance, suggesting allele-specific inactivation. Both MHC-I negative and MHC-I positivemono cases showed a significantly higher mutational burden as well as a higher number of inferred neo-antigens, suggesting co-selection of HLA-I loss and sustained neo-antigen production. Interestingly, the analysis of > 500.000 individuals in two databases revealed homozygosity of germline HLA-I genes in 26-38% of DLBCL patients, a frequency significantly higher than that observed in any other cancer type. In mice, germinal-center B cells lacking HLA-I expression did not progress to lymphoma and were counterselected in the context of oncogene-driven lymphomagenesis, suggesting that additional events are needed to license immune evasion. These results suggest a multi-step process of HLA-I loss including both germ-line and somatic events in DLBCL development, and have direct implications for the pathogenesis and immunotherapeutic targeting of this disease.

  Study EGAS00001005054

• Trial of Late Surfactant for Prevention of Bronchopulmonary Dysplasia: A Study in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide (TOLSURF-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions.Objectives: To assess whether late surfactant treatment in extremely low gestational age newborn (ELGAN, ≤28 week gestation) infants requiring ventilation at 7-14 days safely improves survival without bronchopulmonary dysplasia.Background: Bronchopulmonary dysplasia (BPD) is the most common form of chronic lung disease in children with an estimated 15,000 new cases annually in the United States. BPD affects infants born prematurely, is a major contributor to the cost of prematurity each year, and is associated with long-term pulmonary disability, neurodevelopmental abnormalities and death.Increases in the survival of ELGAN infants have resulted in another form of BPD, which is characterized by impaired alveolar and microvascular development with excess tone and reactivity of airway smooth muscle. Despite treatments to enhance lung maturation, premature infants often need prolonged intubation and mechanical ventilation and/or oxygen support. When mechanical ventilation is required longer than 7 days, BPD results in 70% of surviving ELGAN infants. Most of these infants experience clinical episodes of increased requirement for ventilatory support that are associated with dysfunctional surfactant, which is primarily due to low surfactant protein B (SP-B). In pilot studies of late surfactant treatment in premature infants, there was short-term improvement in SP-B content. These prior studies provided the rationale for a larger clinical trial for later doses of surfactant treatment to prevent episodes of respiratory decompensation and BPD. Participants: 511 infants were eligible for randomization of the 2693 infants screened. Of the 511 infants eligible for randomization, there were 252 infants allocated to the treatment arm and 259 infants allocated to the placebo arm.Design: The study was designed to assess the effect of late doses of surfactant on survival without BPD at 36 weeks post menstrual age (PMA) in ELGAN infants who required intubation and mechanical ventilation between 7 and 14 days of age and were receiving Inhaled nitric oxide (iNO). Infants were stratified within clinical centers and gestational age groups and randomized to treatment with calfactant, a natural surfactant extracted from bovine lung lavage fluid, or a sham procedure.All infants received iNO according to the protocol used in the Nitric Oxide Chronic Lung Disease (NOCLD) trial. A masked syringe containing either a standard dose of calfactant for the treatment group, or air for the placebo group, was administered to the infant behind a screen by staff not involved in providing the infant's clinical care. Monitor and ventilator alarms were turned off during dosing to avoid unblinding of clinical staff. To accommodate research staff availability and infant instability, the dosing interval was not strictly set but could be repeated every 24 – 72 hours up to 5 doses if the infant still required intubation. Dosing could be discontinued by physician request or parental withdrawal from the study. Due to parental preference, the first infant in a multiple birth was randomized according to the randomization schedule and subsequent infants were assigned to the same treatment group. Follow-up to assess pulmonary and neurologic development continued until 2 years of age, with treatment group blinding maintained. The primary outcome was survival without BPD at 36 weeks PMA. Secondary outcomes included BPD at 40 weeks PMA, pulmonary outcome at 12–24 months of age, and neurodevelopmental outcome at 2 years of age. Conclusions: There were no significant differences observed between the treatment group and the control group for survival without BPD at 36 weeks or 40 weeks.

  Study phs003899

• RNA-seq data for study 'Smoking-dependent expression alterations in nasal epithelium reveal immune impairment linked to germline variation and lung cancer risk.'

  RNA-seq data from nasal and bronchial tissues in 649 subjects, many with lung cancer. Lung cancer is the leading cause of cancer-related death in the world. In contrast to many other cancers, a direct connection to lifestyle risk in the form of cigarette smoke has long been established. More than 50% of all smoking-related lung cancers occur in former smokers, often many years after smoking cessation. Despite extensive research, the molecular processes for persistent lung cancer risk are unclear. CT screening of current and former smokers has been shown to reduce lung cancer mortality by up to 26%. To examine whether clinical risk stratification can be improved upon by the addition of genetic data, and to explore the mechanisms of the persisting risk in former smokers, we have analyzed transcriptomic data from accessible airway tissues of 487 subjects. We developed a model to assess smoking associated gene expression changes and their reversibility after smoking is stopped, in both healthy subjects and clinic patients. We find persistent smoking associated immune alterations to be a hallmark of the clinic patients. Integrating previous GWAS data using a transcriptional network approach, we demonstrate that the same immune and interferon related pathways are strongly enriched for genes linked to known genetic risk factors, demonstrating a causal relationship between immune alteration and lung cancer risk. Finally, we used accessible airway transcriptomic data to derive a non-invasive lung cancer risk classifier. Our results provide initial evidence for germline-mediated personalised smoke injury response and risk in the general population, with potential implications for managing long-term lung cancer incidence and mortality.

  Dataset EGAD50000000333