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• Single-cell RNA-Seq of human lymphoma reveals malignant B cell diversity and patterns of T cell immune checkpoint co-expression

  Follicular lymphoma (FL) is a generally incurable B-cell malignancy which has the potential to transform into highly aggressive lymphomas. Genomic studies indicate it is often a small subpopulation rather than the dominant population in the FL that gives rise to the more aggressive subtype. To resolve the underlying transcriptional networks of follicular B-cell lymphomas at single molecule and cell resolution, we leveraged droplet-based barcoding technology for highly parallel single cell RNA-Seq. We analyzed the transcriptomes from tens of thousands of cells derived from five primary FL tumors. Simultaneously, we conducted multi-dimensional flow cell sorting to validate our characterizing of cellular lineages and critical expressed proteins. For each tumor, we identified multiple cellular subpopulations, matching known hematopoietic lineages. Comparison of gene expression by matched malignant and normal B cells from the same patient revealed tumor-specific features. Malignant B cells exhibited restricted immunoglobulin light chain expression (either Ig Kappa or Ig Lambda), as well the expected upregulation of the BCL2 gene, but also down-regulation of the FCER2, CD52 and MHC class II genes. By leveraging the single-cell resolution on large numbers of cells per patient, we were able to examine tumor-resident T cells. We identified pairs of immune checkpoint molecules that were co-expressed, providing a potentially useful strategy for selection of patient-tailored combination immunotherapies. In summary, massively parallel measurement of single-cell expression in thousands of tumor cells and tumor-resident lymphocytes can be used to obtain a systems-level view of the tumor microenvironment and identify new avenues for therapeutic development.

  Study phs001378

• Aspirin and Inflammation: Mutations, Genes, Pathways and Prevention in Barrett's Esophagus

  Background: Use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to protect against tetraploidy, aneuploidy, and chromosomal alterations in the metaplastic condition Barrett's esophagus (BE) and to lower the incidence and mortality of esophageal adenocarcinoma (EA). The esophagus is exposed to both intrinsic and extrinsic mutagens resulting from gastric reflux, chronic inflammation and exposure to environmental carcinogens such as those found in cigarettes. Here we test the hypothesis that NSAID use inhibits accumulation of point mutations/indels during somatic genomic evolution in BE. Methods: Whole exome sequences were generated from 82 purified epithelial biopsies and paired blood samples from a cross-sectional study of 41 NSAID users and 41 nonusers matched by sex, age, smoking, and continuous time using or not using NSAIDs. Results: NSAID use reduced overall frequency of point mutations across the spectrum of mutation types, lowered the frequency of mutations even when adjusted for both TP53 mutation and smoking status, and decreased the prevalence of clones with high variant allele frequency. Never smokers who consistently used NSAIDs had fewer point mutations in signature 17, which is commonly found in EA. NSAID users had on average a 50% reduction in functional gene mutations in nine cancer-associated pathways and also had less diversity in pathway mutational burden compared to nonusers. Conclusions: These results indicate NSAID use functions to limit overall mutations on which selection can act and supports a model in which specific mutant cell populations survive or expand better in the absence of NSAIDs. Galipeau PC, et al. Genome Med. 2018 Feb 27;10(1):17. PMID: 29486792.

  Study phs001654

• Investigating the Role of Neddylation in the Repair of Topoisomerase I-Mediated DNA Damage in Colorectal Cancer

  Colorectal cancer is one of the most lethal cancers worldwide. First-line chemotherapy for metastatic CRC (mCRC) entails a combination of irinotecan with 5-fluorouracil and leucovorin (FOLFIRI). Irinotecan is a prodrug that is converted within the cell to its active metabolite SN38, a potent TOP1 inhibitor. TOP1 relieves DNA torsional strain arising from DNA metabolism by cleaving one strand of the DNA duplex and forming an enzyme-DNA covalent intermediate that can be trapped by inhibitors. The resulting TOP1 DNA-protein crosslinks (TOP1-DPCs) interfere with replication and transcription and induce cell death if left unrepaired. I have established the role of the ubiquitin-proteasome pathway in TOP1-DPC repair, but it remains unknown how ubiquitylation is activated. One possibility is that collision between advancing replication forks and the DPCs triggers a specific ubiquitin ligase to target DPCs for degradation. The DDB1-CUL4 (Cullin 4)-RBX1 (CRL4) ubiquitin ligase complex performs a salient role in both replication and DNA repair upon its activation by auto-NEDD8 modification (neddylation), but it is unknown whether it plays a role for TOP1-DPC repair. We plan to define the role of neddylation for TOP1-DPC repair during replication and examine irinotecan plus pevonedistat (PEV), a NEDD8-activating enzyme inhibitor in multiple clinical trials, in CRC patient-derived preclinical models including 3D organoids. The three in-house organoids, from which samples have been submitted to dbGaP, were sequenced as a means of verifying their identity as colon cancer organoids, to allow us to investigate the combination of TOP1 inhibitors and PEV and the molecular mechanisms underlying this drug combination in these organoids.

  Study phs003257

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

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

  Study phs000910

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

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

  Study phs000971

• Center Common Disease Genomics [CCDG] - Cardiovascular: Partners Biobank

  This study is a part of NHGRI's Center for Common Disease Genomics, a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Current estimates anticipate that the CCDG program will perform whole genome sequencing of 140K individuals and whole exome sequencing of 225K individuals over the course of the project. The Cardiovascular Disease working group of the CCDG considered five diseases: early-onset coronary artery disease (EOCAD), stroke, atrial fibrillation, congestive heart failure and type 2 diabetes. CAD is the leading cause of death in the world and common variant association studies show that our understanding of the underlying molecular mechanisms is incomplete (e.g, >2/3 of the 63 common variants previously mapped for CAD do not directly relate to known risk factors). CAD is representative of a class of common diseases with onset at middle age. When CAD occurs early in life, there is a stronger inherited component. In addition, there is empirical evidence that a burden of rare coding alleles in individual genes contribute to risk for CAD. Source: https://ccdg.rutgers.edu/sites/default/files/CCDG_CVD_EOCAD_STROKE_FINAL.pdf For this study, The Broad Institute of MIT and Harvard generated genetic data for ~13,500 individuals from the Partners Biobank, including using whole exome sequencing and whole genome genotyping (Infinium Global Screening Array), with 550 samples from patients with myocardial infarction, a type of EOCAD. Partners Biobank, launched in 2010, is a biobank composed of samples from Partners hospitals, including Massachusetts General Hospital and Brigham and Women's Hospital. The Biobank has enrolled >100K individuals to study how genes, lifestyle, and other factors affect people's health and contribute to disease.

  Study phs002018

• Integration of Genomics and Transcriptomics in unselected Twins and in Major Depression

  Our goals are to develop a comprehensive understanding of the genomics of transcription in a population based unselected sample and to discover DNA and RNA biomarkers for major depressive disorder (MDD). This work is essential to developing a more complete understanding of the biological basis of MDD, a common complex trait associated with considerable morbidity, mortality, and personal/societal cost. All biological samples have been collected from well-defined populations, and are now available. First, we conduct a "genetical genomics" or eQTL study of ~800 MZ and ~800DZ twin pairs. Each subject has been assayed for genome-wide SNPs and CNVs and gene expression from peripheral blood sampled under standardized conditions. We determine the genetic architecture (genetic and non-genetic proportions of variance via twin analyses) for every transcript, and the genome-wide associations (i.e., SNP-transcript eQTL pairs). These analyses will be expanded to consider transcriptional modules. The key deliverable is a detailed catalogue of the general and specific architecture of transcription plus raw intensity files. Second, we seek to discover DNA and RNA biomarkers relevant to MDD, capitalizing on the results of a large MDD study with repeated clinical and biological assessments; we have previously shown that PB is a reasonable proxy for CNS expression and employ an advanced modelling framework: (a) Using baseline data, we identify biomarkers for MDD by comparing ~1000 controls with ~1400 MDD cases via comparisons of SNP, CNV, expression transcripts, and transcriptional modules. (b) Using longitudinal data, we contrast gene expression signatures assessed at baseline and two years later in ~200 controls and ~500 MDD cases.

  Study phs000486

• A Phase I Study With a Personalized Neoantigen Cancer Vaccine in Glioblastoma Multiforme

  Neoantigens, which are derived from tumor-specific protein-coding gene mutations, are exempt from central tolerance, can generate robust immune responses and function as bona fide antigens that facilitate tumor rejection. A strategy of using multi-epitope and personalized neoantigen vaccination has previously been tested in patients with high-risk melanoma. We demonstrated that this strategy is feasible for glioblastoma (GBM) which typically has a relatively low mutation load and an immunologically 'cold' tumor microenvironment. We conducted whole exome sequencing (WES) of tumor and normal cells from individual GBM patients to identify tumor-specific mutations. We assessed the expression of mutated alleles by RNA-sequencing of tumor, and used personalized neoantigen-targeting vaccines to immunize newly diagnosed GBM patients following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone, a highly potent corticosteroid that is frequently prescribed to treat cerebral oedema in GBM patients, generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses that were enriched in a memory phenotype and showed an increase in the number of tumor-infiltrating T cells. Using single-cell T cell receptor analysis, we provided an evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial GBM tumor. Neoantigen-targeting vaccines thus have the potential to favorably alter the immune environment of GBM.In order to discover cancer antigens derived from annotated and unannotated protein-coding regions of the genome, we carried out matched ribosome profiling (Ribo-Seq) on two GBM samples. We discovered novel or unannotated open reading frames (nuORFs) and their expression levels as well as somatic mutations within the nuORFs, which could be used to predict potential neoantigens.

  Study phs001519

• NHLBI TOPMed: Coronary Artery Risk Development in Young Adults (CARDIA)

  CARDIA is a study examining the etiology and natural history of cardiovascular disease beginning in young adulthood. In 1985-1986, a cohort of 5115 healthy black and white men and women, aged 18-30 years, were selected to have approximately the same number of people in subgroups of age (18-24 and 25-30), sex, race, and education (high school or less, and more than high school) within each of four US Field Centers. These same participants were asked to participate in follow-up examinations during 1987-1988 (Year 2), 1990-1991 (Year 5), 1992-1993 (Year 7), 1995-1996 (Year 10), 2000-2001 (Year 15), 2005-2006 (Year 20), 2010-2011 (Year 25) and 2015-2016 (Year 30). In addition to the follow-up examinations, participants are contacted regularly for the ascertainment of information on out-patient procedures and hospitalizations experienced between contacts. Within the past five years, 95% of the original surviving cohort has been contacted. While the specifics of each examination have differed somewhat, data have been collected on a variety of factors believed to be related to heart disease. These include conditions with clear links to heart disease, such as blood pressure, cholesterol and other lipids. Data have also been collected on physical measurements, such as weight and skinfold fat, as well as lifestyle factors such as substance use (tobacco and alcohol), dietary and exercise patterns, behavioral and psychological variables, medical and family history, and other chemistries (e.g., insulin and glucose). In addition, subclinical atherosclerosis was measured via echocardiography during Years 5, 10, and 25, computed tomography during Years 15 and 20, and carotid ultrasound during Year 20.Comprehensive phenotypic data for study participants are available through dbGaP phs000285.

  Study phs001612

• 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