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• Genomic Characterization CS-MATCH-0007 Arm I

  The CS-MATCH-0007 protocol is part of a collaboration between the Center for Cancer Genomics (CCG) and the Division of Cancer Treatment and Diagnosis (DCTD) to perform whole-exome sequencing and RNA sequencing using pre-and post-treatment tumor biopsy specimens from patients enrolled on a treatment arm of the NCI-MATCH Clinical Trial (EAY131). The goal of this study is to identify the molecular basis for response and resistance to targeted therapies that are matched to specific genomic alterations found in their cancers. Arm I is one of the treatment sub-protocols within the NCI-MATCH Clinical Trial (EAY131) where patients with PIK3CA mutations (without KRAS Mutation or PTEN Loss) are treated with Taselisib. This subprotocol is one of the treatment arms included in the CS-MATCH-0007 protocol and will provide specimens for the program including DNA from tumor tissue and whole blood.

  Study phs002181

• Genomic Characterization CS-MATCH-0007 Arm U

  The CS-MATCH-0007 protocol is part of a collaboration between the Center for Cancer Genomics (CCG) and the Division of Cancer Treatment and Diagnosis (DCTD) to perform whole-exome sequencing and RNA sequencing using pre-and post-treatment tumor biopsy specimens from patients enrolled on a treatment arm of the NCI-MATCH Clinical Trial (EAY131). The goal of this study is to identify the molecular basis for response and resistance to targeted therapies that are matched to specific genomic alterations found in their cancers. Arm U is one of the treatment sub-protocols within the NCI-MATCH Clinical Trial (EAY131) where patients with NF2 loss are treated with Defactinib. This subprotocol is one of the treatment arms included in the CS-MATCH-0007 protocol and will provide specimens for the program including DNA from tumor tissue and whole blood.

  Study phs002179

• Genomic Characterization CS-MATCH-0007 Arm C1

  The CS-MATCH-0007 protocol is part of a collaboration between the Center for Cancer Genomics (CCG) and the Division of Cancer Treatment and Diagnosis (DCTD) to perform whole-exome sequencing and RNA sequencing using pre-and post-treatment tumor biopsy specimens from patients enrolled on a treatment arm of the NCI-MATCH Clinical Trial (EAY131). The goal of this study is to identify the molecular basis for response and resistance to targeted therapies that are matched to specific genomic alterations found in their cancers. Arm C1 is one of the treatment sub-protocols within the NCI-MATCH Clinical Trial (EAY131) where patients with MET amplification are treated with Crizotinib. This subprotocol is one of the treatment arms included in the CS-MATCH-0007 protocol and will provide specimens for the program including DNA from tumor tissue and whole blood.

  Study phs002177

• Genomic Characterization CS-MATCH-0007 Arm Z1B

  The CS-MATCH-0007 protocol is part of a collaboration between the Center for Cancer Genomics (CCG) and the Division of Cancer Treatment and Diagnosis (DCTD) to perform whole-exome sequencing and RNA sequencing using pre-and post-treatment tumor biopsy specimens from patients enrolled on a treatment arm of the NCI-MATCH Clinical Trial (EAY131). The goal of this study is to identify the molecular basis for response and resistance to targeted therapies that are matched to specific genomic alterations found in their cancers. Arm Z1B is one of the treatment sub-protocols within the NCI-MATCH Clinical Trial (EAY131) where patients with CCND1, CCND2, and/or CCND3 amplifications are treated with Palbociclib. This subprotocol is one of the treatment arms included in the CS-MATCH-0007 protocol and will provide specimens for the program including DNA from tumor tissue and whole blood.

  Study phs002180

• Genomic Characterization CS-MATCH-0007 Arm Q

  The CS-MATCH-0007 protocol is part of a collaboration between the Center for Cancer Genomics (CCG) and the Division of Cancer Treatment and Diagnosis (DCTD) to perform whole-exome sequencing and RNA sequencing using pre-and post-treatment tumor biopsy specimens from patients enrolled on a treatment arm of the NCI-MATCH Clinical Trial (EAY131). The goal of this study is to identify the molecular basis for response and resistance to targeted therapies that are matched to specific genomic alterations found in their cancers. Arm Q is one of the treatment sub-protocols within the NCI-MATCH Clinical Trial (EAY131) where patients with HER2 amplification are treated with Kadcyla® (ado-trastuzumab emtansine). This subprotocol is one of the treatment arms included in the CS-MATCH-0007 protocol and will provide specimens for the program including tumor tissue and whole blood.

  Study phs001926

• Etiology of congenital thyroid dysfunction in Down Syndrome: a multi-omics investigation

  The goal of this study was to investigate dfiferences in the thyroid DNA methylome and transcriptome between fetuses with Down syndrome and fetuses with no genetic/developmental abnormality.

  Study EGAS50000000264

• Single cell transcriptomic and genomic profiling of carcinogenesis in patients with familial adenomatous polyposis

  Familial Adenomatous Polyposis (FAP) is characterized by hundreds to thousands of adenocarcinomas at different evolutional stages in the colon and rectum. Much effort has been made to illuminate the key genomic alterations that facilitate the transition from adenoma to carcinoma. However, the strong heterogeneity of the tumors may hamper these efforts. Here, by sequencing matched adjacent normal tissues, adenomas at different stages and carcinomas from the same patient, we precisely traced the process of colorectal carcinogenesis. Our study offers an accurate genomic landscape during the initiation and progression of carcinogenesis, especially for the transition between adenomas and carcinomas.

  Study EGAS00001003598

• Transcriptional profiling of ovarian tumours and cell lines

  Purpose: Endogenous retroviruses (ERVs) play a role in a variety of biological processes, including embryogenesis and cancer. DNA methyltransferase inhibitors (DNMTi)-induced ERV expression triggers interferon responses in ovarian cancer cells via the viral sensing machinery. Baseline expression of ERVs also occurs in cancer cells, though this process is poorly understood and previously unexplored in epithelial ovarian cancer (EOC). Here, the prognostic and immunomodulatory consequences of baseline ERV expression was assessed in EOC. Experimental Design: ERV expression was assessed using EOC transcriptional data from TCGA and from an independent cohort (HH), as well as from untreated or DNMTi-treated EOC cell lines. LASSO logistic regression defined an ERV expression score to predict patient prognosis. Immunohistochemistry (IHC) was conducted on the HH cohort. Combination of DNMTi treatment with γδ T cells was tested in vitro, using EOC cell lines and patient-derived tumor cells. Results: ERV expression was found to define clinically relevant subsets of EOC patients. An ERV prognostic score was successfully generated in TCGA and validated in the independent cohort. In EOC patients from this cohort, a high ERV score was associated with better survival (log-rank p=0.0009) and correlated with infiltration of CD8+PD1+ T cells (r=0.46, p=0.0001). In vitro, baseline ERV expression dictates the level of ERV induction in response to DNMTi. Manipulation of ERV expression by DNMTi resulted in improved EOC cell killing by cytotoxic immune cells. Conclusions: These findings uncover the potential for baseline ERV expression to robustly inform EOC patient prognosis, influence tumor immune infiltration and affect anti-tumor immunity.

  Study EGAS00001004814

• Genesis of Two Most Prevalent Variants Causing Combined Pituitary Hormone Deficiency in 21 Populations

  Two variants (c.[301_302delAG];[301_302delAG] and c.[150delA];[150delA]) in the PROP1 gene are the most common genetic causes of recessively inherited combined pituitary hormones deficiency (CPHD). Our objective was to analyze in detail the origin of the two most prevalent variants. In the multicentric study were included 237 patients with CPHD and their 15 relatives carrying c.[301_302delAG];[301_302delAG] or c.[150delA];[150delA] or c.[301_302delAG];[ 150delA]. They originated from 21 different countries worldwide. We genotyped 21 single nucleotide variant markers flanking the 9.6Mb region around the PROP1 gene that are not in mutual linkage disequilibrium in the general populations - a finding of a common haplotype would be indicative of ancestral origin of the variant. Haplotypes were reconstructed by Phase and Haploview software, and the variant age was estimated using an allelic association method. We demonstrated ancestral origin of both variants: c.[301_302delAG] was carried on 0.2Mb-long haplotype in a majority of European patients arising approximately 101 generations ago (confidence interval 90.1-116.4). Patients from the Iberian Peninsula displayed a different haplotype which was estimated to have emerged 23.3 (20.1-29.1) generations ago. Subsequently, the data indicated that both haplotypes were transmitted to Latin American patients approximately 13.8 (12.2-17.0) and 16.4 (14.4-20.1) generations ago, respectively. The c.[150delA] variant that was carried on a haplotype spanning about 0.3Mb was estimated to appear 43.7 (38.4-52.7) generations ago. We present strong evidence that the most frequent variants in the PROP1 gene are not a consequence of variant hot-spots as previously assumed, but are founder variants.

  Study EGAS00001001165

• Differential Presence of Exons in Cell-Free DNA Reveals Different Patterns in Colorectal Cancer Between Metastatic and Non-Metastatic Patients

  Tumor genotyping during disease follow-up is gaining an increasing interest for monitoring and clinical management in colorectal cancer (CRC). Growing evidences suggest that single biopsies are inefficient for molecular profiling, due to clonal evolution and intratumoral heterogeneity of primary tumors and/or metastasis. Circulating free DNA (cfDNA) has emerged as an alternative source of genetic material that seems to be representative of the continuously changing tumor molecular features. Thus, the so-called 'liquid biopsy' also offers the additional advantages of accessibility and non-invasiveness for the patient. Novel strategies based on next-generation sequencing (NGS) of cfDNA are being currently developed, with most studies focusing on targeted deep sequencing panels of potential clinically actionable genes. Here we describe an alternative approach, consisting of exome-sequencing in cfDNA at a relatively shallower depth to provide a more general overview of the circulating genome. In this study, two groups of colorectal cancer patients, with either disseminated (M) or localized disease (N), were compared using whole-exome sequencing and a RNA-seq bioinformatics analysis pipeline. Thus, a set of 379 exons present at different levels in cfDNA from both groups were identified, giving rise to a completely new concept in this field, termed as 'Differential Presence of Exons'. Differentially present exons (DPEs) were subsequently used for M and N patients clustering and classification, allowing for the design of a predictive algorithm with encouraging preliminary results in a small subset of patients that could not be initially classified attending to the selection criteria (U group, unassignable).

  Study EGAS00001002687

• BAM files: Brain transcriptome of hereditary cerebral haemorrhage with amyloidosis–Dutch type (HCHWA-D)

  cDNA depleted RNA (500ng total RNA input) was fragmented to 150-200 nucleotides in first strand buffer for 3 minutes at 94°C. Random hexamer primed first strand was generated in presence of dATP, dGTP, dCTP and cTTP. Second strand was generated using dUTP instead of dTTP to tag the second strand. Subsequent steps to generate the sequencing libraries were performed with the KAPA HTP Library Preparation Kit for Illumina sequencing with minor modifications, i.e., after indexed adapter ligation to the dsDNA fragments, the library was treated with USER enzyme (NEB_M5505L) in order to digest the second strand derived fragments. After amplification of the libraries, samples with unique sample indexes were pooled and sequenced paired-end 2x50bp on a HiSeq2500 system following standard Illumina guidelines.

  Dataset EGAD00001003806

• Warfarin Pharmacogenetics: Pharmacogenetic Optimization of Anticoagulant Response (POAT) and Genetic and Environmental Determinants of Warfarin Response (GEDWR)

  Although the efficacy of warfarin in the treatment and prevention of thromboembolic disorders is proven, it is vastly underutilized with difficulties in management and risk of complications being the main deterrents. Recognition of genetic regulation of warfarin response has fueled efforts to quantify this influence, but the focus has been restricted to select genes and outcomes mainly in European Americans. Race appears to influence warfarin dose requirements with African Americans requiring larger and Asians requiring lower doses compared to Europeans. This variation in dose requirement by race may at least partially be explained by genetic differences. The Genetic and Environmental Determinants of Warfarin Response (GEDWR) and the Pharmacogenetic Optimization of Anticoagulation Therapy (POAT) are prospective cohort study aimed at defining the influence of CYP2C9, VKORC1 and other genes. All patients were followed at monthly intervals from initiation of therapy. At each visit factors influencing warfarin response such as warfarin dose, INR, concurrent medications, etc. were documented. Information on concurrent medications was updated at every clinic visit by self-report and verified by medical record review. Concomitant use of drugs such as drugs that alter warfarin pharmacokinetics, including CYP2C9 inhibitors (e.g., amiodarone), and pharmacodynamics such as antiplatelet agents (e.g. aspirin). Although the a priori hypothesis focused on the candidate-gene approach, with the recognition that the candidate-gene approach is bound by the assumption that our knowledge of genetic influences on warfarin response is complete. Among African Americans known variation in candidate genes (CYP2C9 and VKORC1) explain substantially less variability in warfarin dose requirements. Therefore a genome-wide association study (GWAS) was conducted on African American patients to identify novel variants associated with warfarin dose requirements.

  Study phs000708

• Identification of the cause of juvenile parkinsonism in a case_SYNJ1

  This study aimed to elucidate the genetic causes underlying the Juvenile Parkinsonism diagnosed in a girl using whole-exome sequencing, analysis of CAG repeats, RNA sequencing analysis on fibroblasts, and metabolite identification. As a result, a homozygous missense mutation SNP T/C (rs2254562) in SYNJ1 and alteration in metabolism were identified.

  Study EGAS00001007686

• Tissue and Fluid Analysis in Ocular Inflammatory Disease

  Granulomas are found in multiple infectious and non-infectious human diseases, yet the pathogenic drivers of granulomatous disease are still poorly understood. To enrich for pathologic inflammatory cells, we leveraged the intrinsic immunologic isolation of the eye by examining granulomatous uveitis, a form of ocular inflammation. We performed single-cell RNA-sequencing to obtain an unbiased gene expression survey of ocular immune cells in the anterior chamber of four live human donors with granulomatous uveitis. We paired this with antigen-receptor sequence analysis to identify clonally expanded lymphocytes. Each individual had robust clonal expansion arising from a single T or B cell lineage, suggesting distinct pathogenic processes in each patient. This variability in clonal expansion was mirrored by individualized combinations of TH1, TH1/TH17, and Tregs in ocular CD4 T cells. In contrast, ocular CD8 T cells were more transcriptionally similar across donors. Finally, clonally expanded, activated B cells displayed evidence of plasmablast differentiation and class-switching within the ocular microenvironment. Collectively, our study identified conserved and individualized features of granulomatous inflammation, illuminating parallel pathophysiologic mechanisms.

  Study phs002449

• 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

• Queensland Melanoma Genomic Biomarker Study

  There is a clinical need to identify melanoma patients not likely to benefit from current targeted and immuno-therapy and identify biomarkers that can predict patient outcome. Genomic biomarkers are not yet part of staging but show promising results. The aim of this study was to determine genomic and image-based biomarkers as adverse prognostic factors in stage III/IV melanoma patients with resected disease. We found combining genomic and PET/CT derived biomarkers with current clinical assessment may offer additional prognostic tools to stratify patients in the clinic.

  Study EGAS00001004619

• Tandem DNA Repeats Activate hTERT Gene Transcription

  Multiple independent sequence variants of the hTERT locus have been associated with telomere length and cancer risks in genome-wide association studies. Here, we identified an intronic variable number tandem repeat, VNTR2-1, as an enhancer-like element, which activated hTERT transcription in a cell and chromatin-dependent manner. VNTR2-1, consisting of 42-bp repeats with an array of E-boxes, cooperated with the proximal promoter in hTERT regulation by bHLH transcription factors and maintained hTERT expression during embryonic stem cell differentiation. Genomic deletion of VNTR2-1 in MelJuSo melanoma cells markedly reduced hTERT transcription, leading to telomere shortening, cellular senescence, and impairment of xenograft tumor growth. Interestingly, VNTR2-1 lengths varied widely in human populations.  To assess the genetic polymorphism of VNTR2-1 in human populations, we analyzed genomic DNA samples of Caucasian Americans and African Americans enrolled in the Georgia Centenarian Study.  VNTR2-1 in these genomic DNA samples were PCR amplified and subjected to sequencing analysis usinb the PacBio® SMRT method. The result showed that all VNTR2-1 alleles in Caucasian Americans contained 76 or more 42-bp repeats, whereas 32% of VNTR2-1 alleles in African Americans had fewer than 76 repeats.  

  Study phs002428

• Somatic_mutation_and_clonal_evolution_in_the_human_testes

  In this study we aim to characterise the landscape of Pathogenic variants and clonal dynamics in normal and cancerous testes and their role in cancer predisposition. The study combines targeted sequencing and whole-genome sequencing of microbiopsies from testes. The range of patients studied will include healthy individuals, and patients with testicular cancer.

  Study EGAS00001003021

• Somatic_mutation_and_clonal_evolution_in_the_human_testes___WES

  In this study we aim to characterise the landscape of Pathogenic variants and clonal dynamics in normal and cancerous testes and their role in cancer predisposition. The study combines targeted sequencing and whole-genome sequencing of microbiopsies from testes. The range of patients studied will include healthy individuals, and patients with testicular cancer.

  Study EGAS00001003023

• TRIGR collaboration between University of Helsinkin and Children's Mercy Research Institute

  DAC for collaborations between by the University of Helsinki and Children's Mercy Hospital, such as the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), used to study the evolving epigenomics of immune cells in type 1 diabetes at single nuclei resolution

  Dac EGAC50000000543

• NGS-based targeted exome sequencing of osteosarcoma

  The present study aimed to identify potential genomic markers for the prediction of chemosensitivity in patients with OS using a genomic approach.

  Study JGAS000282

• Elucidation of molecular mechanism of NAFLD-HCC

  We aimed to elucidate the interaction between cancer cells and immune cells in the tumor immune microenvironment of non-viral hepatocellular carcinoma.

  Study JGAS000311

• Low_coverage_whole_genome_sequencing_of_samples_from_the__Cretan_Greek_isolate_collection_HELIC_MANOLIS

  Whole-genome sequencing at 1x of samples from the Cretan Greek isolate collection HELIC-MANOLIS. Genome-wide association studies of complex traits have been successful in identifying common variant associations, but a substantial heritability gap remains. The field of complex trait genetics is shifting towards the study of low frequency and rare variants, which are hypothesised to have larger effects. The study of these variants can be empowered by focusing on isolated populations, in which rare variants may have increased in frequency and linkage disequilibrium tends to be extended. This work focuses on an isolated population from Crete, Greece. Sequencing is very efficient in isolated populations, because variants found in a few samples will be shared by others in extended haplotype contexts, supporting accurate imputation.

  Study EGAS00001000392

• Ultrasensitive detection of minor allele fractions in maternal samples based on microhaplotype analysis

  Background: Tools for quantifying and studying genetic variation in heterogeneous cell populations have a limited sensitivity. However, many biological problems require ultrasensitive genetic deconvolution of cell mixtures. The detection of fetal cells in cervical samples from pregnant women presents such a challenge. Methods: Using deep sequencing of microhaplotype loci and analysis of the error profiles in genetically pure and mixed samples, we increase the sensitivity for minor allele detection and demonstrate the potential for paternal allele detection in cervical samples from pregnant women. Results: Using artificial DNA mixtures, we show that unique alleles can be readily identified in mixtures with a ratio of 1 in 10,000 (0.01%). By applying this method on ten non-invasive cervical samples from pregnant women we could identify the presence of paternal alleles in half of the samples. Unexpectedly, we demonstrate those alleles not to be of fetal origin but of sperm. Conclusions: We developed a novel method that can deconvolute genetic mixtures to at least 0.01%, which can be applied to study minor allele fractions in genetic mixtures and, for example, could aid in trophoblast cell detection in maternal blood or cervix. Our results demonstrate the importance of discriminating fetal and paternal alleles when analyzing cervical fetal cells and may pinpoint a potential cause of erroneous results in previous trophoblast isolation studies.

  Study EGAS00001007057

• Molecular defects in pseudohypoparathyroidism or related disorders

  Maintaining calcium levels within a narrow normal range is of critical importance for numerous different cellular functions. One of the most important regulators of blood calcium levels is parathyroid hormone (PTH), which mediates its actions through the PTH/PTHrP receptor, a Gαs-coupled receptor. Few inherited disorders are characterized by diminished blood calcium levels and elevated blood phosphate levels; some of these disorders are caused by too little PTH synthesis and/or secretion (hypoparathyroidism, HP), while others are caused by resistance towards PTH (pseudohypoparathyroidism, PHP). Only few of the inherited forms of HP (<10%) have been defined at the molecular level. In contrast, genetic mutations have been identified for several inherited forms of PHP. For example, PHP type Ia (PHP-Ia) is caused by maternally inherited mutations in those GNAS exons that encode Gαs, while autosomal dominant PHP type Ib (AD-PHP-Ib) is caused by maternal inherited deletions within or up-stream of GNAS, which are associated with abnormal GNAS methylation. However, a large number of patients with PTH-resistance and thus hypocalcemia show GNAS methylation changes, but their underlying genetic defects have not yet been defined at the DNA level. These "sporadic" patients may be affected by an autosomal recessive form of PHP-Ib (AR-PHP-Ib), which is most likely not linked to the GNAS locus. In our studies, we propose to search through exome sequence analyses for novel genetic mutations responsible for novel autosomal dominant forms of HP that are not caused by mutations in the known disease-causing genes; some of these families are large enough to perform genetic linkage studies. We furthermore propose to search for the genetic mutation(s) responsible for the autosomal recessive variant of PHP-Ib through the analysis of whole exome sequences; for these studies we focus particularly on patients, whose parents are likely to be consanguineous. The proposed efforts are expected to lead to the identification of novel genes that are involved in parathyroid development and function (HP) and genes that are involved in the establishment or maintenance of GNAS methylation (AR-PHP-Ib).

  Study phs000476