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• Genomic Predictors of Combat Stress Vulnerability and Resilience

  The Genomic Predictors of Combat Stress Vulnerability and Resilience Study was designed to probe the likely hereditary basis for risk or resilience to develop PTSD and other trauma spectrum disorders. The overall guiding hypothesis was that genomic variation gives rise to risk/susceptibility traits that, when actuated by traumatic environmental stimuli, such as combat, give rise to PTSD and other stress-related phenotypes. Two studies designed to identify risk and resilience factors for combat-induced, stress-related symptoms are being conducted by our group: The Marine Resiliency Study (MRS) is a prospective PTSD study with longitudinal follow-up (pre- and post-exposure to combat stress) of US Marines bound for deployment to Iraq or Afghanistan. Extensive phenotyping includes 3 domains: Psychosocial, Psychophysiologic, and Biophysiologic. The biological and physiological measures collected were chosen in part due to their potential to serve as intermediate phenotypes for stress-related disorders. A second, cross-sectional study involves a cohort of combat-exposed active duty or previously deployed service members (CAVC), including PTSD cases and controls with comparable psychosocial and clinical phenotypes. Little information is available about the factors that explain why some trauma survivors develop stress disorders and some do not. It is hoped that the insights gained from this approach will improve understanding of the genetic contributors to PTSD, and potentially provide novel diagnostic tests and therapeutic approaches to this currently enigmatic and difficult-to-manage condition.

  Study phs000864

• Kids First Pediatric Research Study in Familial Predisposition to Hematopoietic Malignancies (SJFAMILY-HM)

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). All of the WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Acute lymphoblastic leukemia (ALL) is the commonest childhood tumor and a leading cause of cancer death in children, adolescents and young adults. Hodgkin and non-Hodgkin lymphoma are also important hematologic malignancies (HM) that occur in children. Each are genetic diseases with growing evidence for a germline predisposition of both familial and sporadic cases, however the inherited genetic basis of ALL/lymphoma are poorly understood. Such knowledge is essential to gain mechanistic insight into the basis of tumor formation, and to guide genetic counseling and genetic management. Here we have assembled a large collection of familial HM kindreds, and extended recurrence cohorts of ALL and HL which will be used to identify the genetic basis of familial HM, examine the frequency of germline variants in sporadic ALL and HL, and to integrate inherited and somatic genomic data. These studies have high potential to provide fundamental new insights into the inherited genetic basis of HM, to provide important information to guide clinical management, and to provide an invaluable public resource of genomic data.

  Study phs001738

• 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

• 1 Intratumoral genetic heterogeneity and clonal evolution following neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal tumors.

  Purpose: Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment forpatients with locally advanced rectal cancer. However, little is known about the effect of nCRT in the mutational landscape and intratumoral genetic heterogeneity (ITGH) of rectal tumors. Moreover, response to nCRT vary substantially among patients and the genetic determinants of treatment response are not fully understood. Here, we sought to determine the impact of nCRT in the mutational landscape and ITGH of rectal tumors and to identify putative drivers of therapeutic resistance. Patients and Methods: We analyzed whole-exome sequencing (WES) and clinical data from 79 primary non-treated rectal cancers obtained from The Cancer Genome Atlas (TCGA). We also compared the mutational landscape of a matched set of peripheral blood cells, irradiated tumor-adjacent colonic mucosa and pre and post-treatment tumor samples to determine the iatrogenic effects of nCRT and its impact in tissue genetic heterogeneity. Finally, we performed WES of 7 matched pre and post-treatment tumor samples to examine how nCRT affects the clonal architecture of rectal tumors. Results: We show that rectal tumors exhibit remarkable ITGH, which increases with disease progression. We also show that nCRT, per se, does not introduce novel somatic mutations, nor alters the clonal architecture of the irradiated colonic mucosa. Instead, we show that it acts as a potent selective pressure, favoring the expansion of tumor cell subpopulations more prone to resist therapy and increasing ITGH in the residual tumor. Conclusion: Our results reveal the highly heterogeneous and dynamic clonal architecture of rectal tumors undergoing nCRT. Our results also uncover putative genetic determinants of response to nCRT and a possible role for ITGH in predicting treatment outcome.

  Study EGAS00001003250

• Multimodal Analysis for Human Ex Vivo Studies Shows Extensive Molecular Changes from Delays in Blood Processing

  Multi-omic profiling of human peripheral blood is increasingly utilized to identify biomarkers and pathophysiologic mechanisms of disease. The importance of these platforms in clinical and translational studies led us to investigate the impact of delayed blood processing on the numbers and state of peripheral blood mononuclear cells (PBMC) and on the plasma proteome. Similar to previous studies, we show minimal effects of delayed processing on the numbers and general phenotype of PBMCs up to 18 hours. In contrast, profound changes in the single-cell transcriptome and composition of the plasma proteome become evident as early as 6 hours after blood draw. These reflect patterns of cellular activation across diverse cell types that lead to progressive distancing of the gene expression state and plasma proteome from native in vivo biology. Differences accumulating during an overnight rest (18 hours) could confound relevant biologic variance related to many underlying disease states.

  Study phs002280

• Somatic mutation and selection at epidemiological scale - TwinsUK_TargetedNanoSeq_Buccal

  Targeted NanoSeq in buccal epithelium obtained longitudinally from a number of donors. A custom-designed panel of ~200 genes will be used to achieve high depth coverage (aiming for ~1000X at panel sites).As we age, many tissues become colonised by microscopic clones carrying somatic driver mutations. Some of these clones represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding of the clonal landscapes of human tissues, and their impact on cancer risk, ageing and disease, remains limited due to the challenge of detecting somatic mutations present in small numbers of cells. Here, we introduce a new version of nanorate sequencing (NanoSeq), a duplex sequencing method with error rates of less than 55 per billion base pairs, which is compatible with whole-exome and targeted gene sequencing. Deep sequencing of polyclonal samples with single-molecule sensitivity enables the simultaneous detection of mutations in large numbers of clones, yielding accurate somatic mutation rates, mutational signatures and driver mutation frequencies in any tissue. Applying targeted NanoSeq to 1,042 non-invasive samples of oral epithelium and 371 samples of blood from a twin cohort, we found an unprecedentedly rich landscape of selection, with 46 genes under positive selection driving clonal expansions in the oral epithelium, over 62,000 driver mutations, and evidence of negative selection in some genes. The high number of positively selected mutations in multiple genes provides high-resolution maps of selection across coding and non-coding sites, a form of in vivo saturation mutagenesis. Multivariate regression models enable mutational epidemiology studies on how carcinogenic exposures and cancer risk factors, such as age, tobacco or alcohol, alter the acquisition and selection of somatic mutations. Accurate single-molecule sequencing has the potential to unveil the polyclonal landscape of any tissue, providing a powerful tool to study early carcinogenesis, cancer prevention and the role of somatic mutations in ageing and disease.

  Dataset EGAD00001015618

• Comprehensive cancer predisposition gene testing in an adult multiple primary tumor series shows a broad range of deleterious variants and atypical tumor phenotypes

  Multiple primary tumors (MPT) affect a substantial proportion of cancer survivors and may result from various causes including inherited predisposition. Currently, germline genetic testing of MPT cases for cancer predisposition gene (CPG) variants is mostly targeted by tumor type. We ascertained pre-assessed MPT cases from genetics centers (defined as ≥2 primaries by age 60 years or ≥3 by 70) and performed whole genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment/molecular investigations, pathogenic variants in moderate and high-risk CPGs were detected in 67/440 (15.2%) of probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies including structural variants at low frequency (6/440 (1.4%) of probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant) the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice site CPG variants and at least one discordant tumor type was significantly higher than a control population (χ2=43.642 P=<0.0001). 2/67 (3%) of probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Summing together variant detection rates from a similarly ascertained previous MPT case series, the present results suggest that first-line comprehensive CPG analysis in a clinical genetics referral-based MPT cohort would detect a deleterious variant in about a third of cases.

  Dataset EGAD00001004088

• Exome sequencing of UK Birth Cohorts - Born in Bradford

  Birth cohort studies involve repeated surveys of large numbers of individuals from birth and throughout their lives. They collect information useful for a wide range of life course research domains, and biological samples which can be used to derive data from an increasing collection of omic technologies. This rich source of longitudinal data, when combined with genomic data, offers the scientific community valuable insights from population genetics to rare disease associations. Avon Longitudinal Study of Parents and Children (ALSPAC)recruited 14,775 babies of predominantly White ethnicity in the Avon county of south-west England between 1991 and 1992. Born in Bradford (BiB) is similarly focused on a particular local area, the city of Bradford in the north of England, and recruited 13,858 babies between 2007 and 2011, of whom ~41% self-report as white British and ~59% as other ethnicities, predominantly Pakistani. Millennium Cohort Study (MCS) is a national cohort that recruited 18,827 children born between 2000 and 2002, intentionally over-sampling areas with high child poverty, large ethnic minority populations, and smaller UK nations (Wales, Scotland and Northern Ireland) Available here is a subset of exome-sequenced parents and children from these studies (CRAMS and post-QC VCFs) as detailed in https://doi.org/10.12688/wellcomeopenres.22697 [doi.org]. Phenotypic data is also available by submitting an application to the corresponding cohort: https://borninbradford.nhs.uk/ [borninbradford.nhs.uk]

  Dataset EGAD00001015370

• Assessing Individual Head and Neck Squamous Cell Carcinoma Patient Response to Therapy Through Integration of Functional and Genomic Data

  This study combines RNA sequencing (RNASeq), whole exome sequencing (WES), reverse phase protein array (RPPA) and copy number variation (CNV) data, along with a custom high throughput inhibitor assay to characterize tumor cells from patients with head and neck squamous cell carcinoma (HNSCC), in order to identify potential therapy targets on an individual patient basis. The data that will be available through dbGaP include the RNASeq, WES, RPPA and array CNV data for the tumor and matched normal samples. This study represents a proof-of-concept. No treatments were administered to patients as part of this study.

  Study phs003456

• Single-Cell Transcriptomic Characterization of Microscopic Colitis

  Patients with microscopic colitis (MC), chronic diarrhea without histological signs of MC, or unaffected controls were profiled using single-cell RNA sequencing (scRNA-seq; inDrops and 10X Genomics were used). One profiled patient without clinical symptoms was found to have histological signs of MC (asymptomatic MC). Some of the subjects from dbGaP study phs003418 are controls in this study. T-Cell Receptor sequencing (TCR-Seq) was also performed on a subset of patients. Individual transcriptomes were analyzed to characterize the cellular profile associated with MC and search for mediators of disease pathology. Raw reads and processed count matrices will be available through dbGaP.

  Study phs003876