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• The neo-open reading frame peptides that comprise the tumor framome are a rich source of neoantigens for cancer immunotherapy

  Identification of immunogenic cancer neoantigens as targets for therapy is challenging. Here, we integrate whole genome and long-read transcript sequencing of cancers to identify the collection of neo-open reading frame peptides (NOPs) expressed in tumors. We termed this collection of NOPs the tumor framome. NOPs represent tumor-specific peptides that are different from wild-type proteins and may be strongly immunogenic. We describe a class of hidden NOPs that derive from structural genomic variants involving an upstream protein coding gene driving expression and translation of non-coding regions of the genome downstream of a rearrangement breakpoint, i.e. where no gene annotation or evidence for transcription exists. The entire collection of NOPs represents a vast number of possible neoantigens particularly in tumors with many structural genomic variants and a low number of missense mutations. We show that NOPs are immunogenic and epitopes derived from NOPs can bind to MHC class I molecules. Finally, we provide evidence for the presence of memory T cells specific for hidden NOPs in peripheral blood from a patient with lung cancer. This work highlights NOPs as a major source of possible neoantigens for personalized cancer immunotherapy and provides a rationale for analyzing the complete cancer genome and transcriptome as a basis for detection of NOPs.

  Study EGAS00001006021

• Notch Signaling and Efficacy PD-1/PD-L1 Blockade in Relapsed Small Cell Lung Cancer

  Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine (NE) cancer that accounts for approximately 15% of all lung cancer, with an annual incidence of more than 34,000 in the United States alone. SCLC is characterized by loss of function of p53 and RB and high tumor mutational burden, which suggests that these tumors could be immunogenic and respond to immune checkpoint blockade (ICB). However, the benefit from ICB in an unselected SCLC population is modest. In this study, we evaluated the genomic features associated with clinical outcomes in relapsed SCLC to gain insight into the underlying mechanisms of ICB response. Exome, RNA and TCR sequencing data from a prospective clinical trial of relapsed SCLC treated with durvalumab and olaparib and RNA-sequencing data for second cohort of relapsed SCLC cohort treated with nivolumab are included.   

  Study phs002176

• NHLBI TOPMed - NHGRI CCDG: Atherosclerosis Risk in Communities (ARIC)

  Participants from the Atherosclerosis Risk in Communities (ARIC) Study, a large population-based longitudinal cohort study, have been included in this Project and whole genome sequencing will be performed to contribute to analyses of early-onset atrial fibrillation and venous thromboembolism. Additional phenotype and genotype data are available for these individuals on dbGaP and can be accessed through the parent ARIC Cohort accession (phs000280). The National Heart, Lung and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program is designed to generate scientific resources to enhance understanding of fundamental biological processes that underlie heart, lung, blood and sleep disorders (HLBS). It is part of a broader Precision Medicine Initiative, which aims to provide disease treatments that are tailored to an individual's unique genes and environment. TOPMed will contribute to this initiative through the integration of whole genome sequencing (WGS) and other -omics (e.g., metabolic profiles, protein and RNA expression patterns) data with molecular, behavioral, imaging, environmental, and clinical data. In doing so, this program seeks to uncover factors that increase or decrease the risk of disease, identify subtypes of disease, and develop more targeted and personalized treatments. The Whole Genome Sequencing (WGS) Project is part of NHLBI's TOPMed program and serves as an initial step for the larger initiative.

  Study phs001211

• NHLBI and NIDDK Sponsored GWAS in Benign Ethnic Neutropenia/Leukopenia (BEN) in African-Americans (age >45 yrs old) from the REGARDS

  Benign ethnic neutropenia (BEN) is a clinical condition more commonly observed in African-Americans. It is characterized by a relative reduction in neutrophil count by about 1000 cells per microliter, leading to a decrease in total leukocyte count by similar decrement. Previous reports of this condition showed that there was neither higher frequency nor increased severity of infections in affected individuals. Bone marrow examinations showed normal white cell maturation; and ex vivo culture of marrow cells showed low normal or slightly reduced number of myeloid colonies. Under physiologic stress, the increases in neutrophil and leukocyte counts of BEN individuals are slightly lower, compared to normal African-Americans or Caucasians. These clinical observations suggest that BEN results from a lower 'set point' for cell number in the marrow. Additionally, case reports of familial BEN, the persistence of BEN over many decades in the US, UK, and Africa, and the recent report of Duffy antigen and chemokine receptor (DARC) being associated with neutropenia, all suggest a strong genetic association to neutropenia/leukopenia. Our initial look into microarray analyses in a pilot trial of subjects showed that there were no significant differences in mRNA signals between BEN and normal subjects. Therefore, we are now proposing a larger study, utilizing Illumina Omni Express chips, to look for genetic associations. We have partnered with the Reasons for Geographic and Racial Differences in Stroke study (REGARDS), where nearly half of the cohort are African-Americans. This will be one of the few GWAS being performed in only African-Americans, and will provide valuable genetic information to link with neutropenia and possibly other conditions/diseases. Genotyping was performed by the Johns Hopkins University Center for Inherited Disease Research (CIDR). Quality control of the genotypic and phenotypic data was performed through a collaboration between CIDR and the Genetics Coordinating Center, Department of Biostatistics at the University of Washington, which is funded by a federal contract supported by 14 NIH Institutes (HHSN268200782096C).

  Study phs000507

• Exploring the Genetic Variants Associated with Brain Growth in Children

  Understanding the genetic factors that control brain growth during childhood and adolescence is a priority for neuroscience. Its importance lies partly in the finding that disturbances in the course of brain development characterizes many common childhood behavioral problems. Recent advances in neuroimaging such as the use of non-invasive magnetic resonance imaging have provided a chance to define these trajectories in the living child. The intramural programs of the NIMH and NHGRI have conducted repeated neuroanatomic imaging on children along with the banking of DNA, providing a cohort which is studied for defining developmental trajectories of the brain. A central goal of this cohort is to define the disturbances in brain development that are linked with common behavioral problems, such as excessive impulsivity, hyperactivity and inattention. Studies have demonstrated that problems in these domains are distributed across the entire population and that children with Attention Deficit Hyperactivity Disorder (ADHD) lie at the extreme end of these behavioral dimensions. We found a similar dimensionality in the development of brain regions that are associated with these behavioral problems. Specifically, we showed that the rate of change in both the lateral prefrontal cortex and interconnected striatum during childhood and adolescence was linked to the severity of symptoms of hyperactivity and impulsivity. As symptoms increased, the rate of growth of both structures decreased. The lateral prefrontal cortex and striatum are core components of richly interconnected 'loops' that support a host of cognitive processes, including attention, cognitive control and motor planning. Anomalies in these structures and their connections have been implicated in many childhood behavioral problems, including ADHD. In summary, we aim to identify the common and rare genetic variants that are associated with the developmental trajectories of the lateral-prefrontal cortex and striatum. Identifying genetic variants influencing the growth of these structures may reveal the biological mechanisms underlying dysregulated control of attention, impulse and activity level, which in the extreme constitute ADHD. The study thus could inform our understanding of neurobiology underpinning one of the most common neuropsychiatric disorders of childhood.

  Study phs000962

• Anaplastic Oligodendroglioma AO Exome-seq data

  Anaplastic oligodendrogliomas (AOs) are rare primary brain tumors which are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosome 1p/19q co-deletion and IDH mutation. We analyzed 51 AOs by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall 7.5% of AO are mutated for TCF12, which encodes an oligodendrocyte-related transcription factor. 80% of TCF12 mutations identified were in either the bHLH domain, which is important for TCF12 function as a transcription factor, or were frame shift mutations leading to TCF12 truncated for this domain. We show that these mutations compromise TCF12 transcriptional activity and are associated with a more aggressive tumor type. Our analysis provides further insights into the unique and shared pathways driving AO.

  Dataset EGAD00001001452

• RNA-Seq of PBMC's from rUTI Patients and Healthy Controls

  Recurrent urinary tract infections (rUTIs) are a major health burden worldwide, with history of infection being a significant risk factor. While the gut is a known reservoir for uropathogenic bacteria, the role of the microbiota in rUTI remains unclear. We conducted a year-long study of women with and without history of rUTIs, from whom we collected urine, blood and monthly fecal samples for multi-omic interrogation. The rUTI gut microbiome was significantly depleted in microbial richness and butyrate-producing bacteria compared to controls, reminiscent of other inflammatory conditions, though Escherichia coli gut and bladder dynamics were comparable between cohorts. Blood samples revealed signals of differential systemic immunity, leading us to hypothesize that rUTI susceptibility is in part mediated through a syndrome involving the gut-bladder axis, comprising gut dysbiosis and differential immune response to bacterial bladder colonization, manifesting in symptoms. This work highlights the potential for microbiome therapeutics to prevent and treat rUTIs.  (Reprinted from medrxiv.org ) 

  Study phs002728

• Exome Sequencing to Identify Medically Relevant Associations in Finnish Sub-Isolate Samples from the FINRISK Cohort

  We propose to undertake, at the McDonnell Genome Institute of Washington University, a collaborative exome sequencing project of ~10,000 samples from a large Finnish population cohort, FINRISK, a participating component of the Sequencing Initiative Suomi (SISu) consortium. Together these sequenced samples will provide a unique resource for identification of infrequent or rare variants with a large impact on cardiovascular and metabolic disorders as well as on a wide range of heritable, disease-related quantitative phenotypes. Our collaborative group has already shown, in exome sequencing studies of smaller Finnish samples, that numerous loss of function variants are dramatically more frequent in Finland compared to other European populations, and that such variants demonstrate strong associations to several disease-related traits. Finland is the largest population isolate in Europe and the enrichment of these variants reflects its rapid growth from a severe population bottleneck about 100 generations ago. Northern and Eastern parts of Finland experienced additional, more recent bottlenecks, and therefore the enrichment of particular high-impact variants in these regions is even more extreme (Stoll et al., 2013, PMID: 23912948). We therefore propose to focus exome sequencing efforts on about 10,000 members of FINRISK who are specifically drawn from these sub-isolate regions. As a very wide range of phenotypes are available from this cohort (including cardiovascular and metabolic disease outcomes obtained from national registries) we hypothesize that the proposed exome sequencing will identify numerous new disease-related associations. Within the National Biobanks of Finland (www.nationalbiobanks.fi) we have DNA and tissue samples from over 200,000 individuals of whom 50,000 have GWAS data; these samples provide an exceptional resource for both imputation from the sequencing studies proposed here, as well as for replication of associations.

  Study phs000756

• Genomic Alterations in Gingivo-buccal Cancer: ICGC-India Project_YR01

  As a part of the ICGC, India has undertaken genomic studies on gingivobuccal cancer of the oral cavity, which is the most prevalent form of cancer among men in India. There are various known environmental (life-style) correlates of this cancer, the most important of which are tobacco chewing and HPV infection. Paired DNA samples – isolated from the tumor tissue and from the blood of fifty patients – have been analyzed to catalog germline and somatic mutations. Association between each observed genomic alteration and exposure to environmental risk factors is being explored.Detailed clinical characterization of the patients, collection of data on demographic and environmental exposures, and isolation of DNA samples from blood and tumor tissues collected from each patient are being done at the Advanced Centre for Research, Treatment and Education on Cancer, Mumbai. Exome capture and deep resequencing are being performed at the National Institute of Biomedical Genomics, Kalyani. We have analyzed the exomes of paired blood and tumor DNA samples using two orthogonal platforms – exome capture by Roche-Nimblegen SeqCap Ez kit followed by sequencing on Roche-454 GS FLX, and exome capture by Illumina TrueSeq Exome Enrichment kit followed by sequencing on Illumina HiSeq-2000. Each exome is being sequenced at a mean depth of 30x. In addition, we have used Illumina Omni Quad SNP-chips to generate genotype data at 1.14 million genomic markers. The average concordance between SNP-chip and sequence data is 99.8%.

  Study EGAS00001000249

• Identifying transcriptional programs underlying anti-EGFR small molecule response and resistance with TraCe-seq

  To QC the TraCe-seq strategy, single-cell RNA-seq libraries were generated from a variety of human cancer cell lines transduced with the TraCe-seq library to validate the TraCe-seq strategy. Specifically, 5 different cell lines (PC9, MCF-10A, MDA-MB-231, NCI-H358, and NCI-H1373) were each transduced with a unique TraCe-seq barcode. The transduced cells were selected with puromycin only, dissociated to single cell suspensions, and then mixed together. The complex mixture of the 5 cell lines was profiled by 10X scRNA-seq. Furthermore, transduced NCI-H1373 cells were sorted by FACS to enrich for the top 50% of eGFP positive cells, and sorted cells were cultured briefly and used to construct scRNA-seq libraries and profiled by 10x scRNA-seq. To carry out the full TraCe-seq experiment, ~600 PC9 cells carrying unique TraCe-seq barcodes were expanded over 12 doublings to establish the barcoded population. A subset of the barcoded PC9 population was used to generate scRNA-seq libraries and profiled by 10x scRNA-seq prior to treatment to establish a baseline transcription profile for each barcoded clone. The rest of the cells were then treated for four days with 1 µM erlotinib, 1 µM GNE-069, or 1 µM GNE-104 respectively. scRNA-seq libraries were then generated form the treated cells and profiled by 10x scRNA-seq.

  Dataset EGAD00001007872