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• Standard epigenome mapping in human epithelial cells of the digestive and urogenital organs [ ChIP-Seq ]

  The aim of this study is to participate in International Human Epigenome Consortium (http://ihec-epigenomes.org/), through disclosure of quality reference epigenome profiles in normal and diseased cells obtained from multiple Japanese people.

  Study JGAS000079

• Standard epigenome mapping in human epithelial cells of the digestive and urogenital organs [BS-Seq ]

  The aim of this study is to participate in International Human Epigenome Consortium (http://ihec-epigenomes.org/), through disclosure of quality reference epigenome profiles in normal and diseased cells obtained from multiple Japanese people.

  Study JGAS000078

• Standard epigenome mapping in human epithelial cells of the digestive and urogenital organs [RNA-Seq ]

  The aim of this study is to participate in International Human Epigenome Consortium (http://ihec-epigenomes.org/), through disclosure of quality reference epigenome profiles in normal and diseased cells obtained from multiple Japanese people.

  Study JGAS000081

• G3BP2-KIT drives leukemia amenable to kinase inhibition in Ph-like ALL

  We describe a patient with Ph-like ALL, in which leukemic cells harbored an in-frame fusion between the GTPase-activating protein (SH3 domain)-binding protein 2 (G3BP2) and the KIT proto-oncogene.

  Study EGAS00001005181

• PCCRC versus prevalent CRC

  To analyse genome wide DNA copy number changes in combination with mutation status of CRC-related genes, CIMP and MSI, in order to explore the biology of PCCRCs. Formalin-fixed, paraffin-embedded samples from 122 PCCRCs and 98 prevalent CRCs collected in 3 different hospitals in the region of South Limburg, the Netherlands, were used in this study. DNA was extracted for molecular analysis. Labels have been updated.

  Dataset EGAD00001006987

• National Cancer Institute (NCI) Adding Hispanics to Ongoing GWAS in Colorectal Cancer

  Genome-wide association studies (GWAS) of colorectal cancer (CRC) have been instrumental in identifying a number of common susceptibility loci in Non Hispanic (NH)-White populations, and a NCI priority is to extend GWAS findings to other populations to address racial/ethnic disparities in cancer susceptibility. Currently, GWA studies of CRC in NH-Whites, Japanese and African-Americans are ongoing. We propose a complementary study to address this critical research area in Hispanics. Hispanics represent the fastest growing ethnic population in the U.S. and have been largely understudied in terms of genetic susceptibility to cancer. There are noted differences in incidence, survival and mortality in CRC by ethnic/racial groups. Hispanics often present with CRC at a younger age and have a significantly greater incidence of stage IV tumors or metastatic disease compared to NH-Whites. We propose to conduct a large, cost-efficient, population-based GWAS in Hispanics by building upon existing NIH-funded resources, the Colon Cancer Family Registry (Colon CFR) and the Multiethnic Cohort Study (MEC). We plan to recruit 2,500 Hispanic men and women diagnosed with CRC between 01/2008 to present using cancer registries in California, physican referrals and familial referrals. Risk factor/diet questionnaires, pathology reports, Oragene saliva samples (for genotyping), optional blood samples (for genotyping and biometric analysis) and tumor blocks (for MSI testing) will be collected using methodologies developed in the Colon CFR/MEC. Cases of CRC in the MEC (currently 473; anticipated 600 at end) will also be included. Population-based Hispanic individuals without a diagnosis of CRC participating in other GWA studies in the MEC (n=3,900, U01HG004726, Haiman) will be used as controls. We will genotype all 3,100 cases using the Illumina 1M array and use available genotype and epidemiologic data collected on 3,900 controls. Our statistical analyses will include: single-SNP and haplotype effects, gene-environment interactions and heterogeneity by MSI, tumor subtype and family history of CRC. We will replicate findings in a second-stage using CRC cases and controls from Mexico (1,000 cases and 1,000 controls, EU FP7 funding, CHIBCHA, Carvajal-Carmona/Tomlinson). We will also examine heterogeneity of the risk estimates by ethnicity/race by leveraging GWA data on NH-Whites (2,142 cases, 1,909 controls, U01 CA122839, Casey), (4,000 cases, 6,000 NH-White controls, UK-CHIBCHA, Tomlinson), Colombians (2,000 cases and 2,000 controls, CHIBCHA), Japanese (1,000 cases and 1,000 controls) and African-Americans (1,500 cases and 1,500 controls, R01CA126895, Le Marchand). We will genotype replicated significant SNPs in our main and combined analysis in several Hispanic populations (note: studies funded by EU or NIH for data collection but not GWAS), including 800 Puerto Ricans, 2,000 Brazilians, 2,000 Argentineans and 3,000 Spanish/Portuguese, to assess generalizability of findings. We will examine the differences in inflammatory gene transcription dynamics in leukocytes (from blood sample collection) by fatigue level (as assessed from study questionnaire data). This study will have a high impact by addressing the key question of racial/ethnic disparities related to genetic susceptibility to CRC, will provide translational guidelines on biological mechanisms during the cancer survivorship period to increase quality of life among cancer survivors, and will enable further growth and investment into research among Hispanics by providing a resource of genetic data and biospecimens, which is lacking.

  Study phs001193

• Transcriptomic Profile of Whole Blood Cells from Elderly Subjects fed Probiotic Bacteria Lactobacillus rhamnosus GG ATCC 53103 (LGG) in a Phase I Open Label Study

  Open label study to evaluate the safety of Lactobacillus rhamnosus GG ATCC 53103 (LGG) in elderly subjects. Fifteen healthy elderly volunteers, ages 65-80 were enrolled in a study in which they received LGG capsules containing 1 x 1010 CFU, twice daily for 28 days and were followed through day 56. The study subjects completed a daily diary, a telephone call on study days 3, 7 and 14 and study visits at the Massachusetts General Hospital Clinical Research Center at baseline, day 28 and day 56. During each visit, the subject diary, interim history, potential adverse effects and concomitant medications were reviewed and vital signs and a physical examination were performed. Routine blood tests were obtained to monitor for safety during visits and nasopharyngeal and stool samples were collected for microbiome analysis. Volunteers interested in participating in the effect of LGG probiotic on the Human whole Blood Transcriptome substudy also had blood drawn for DNA and RNA extraction, after signing the substudy consent form. The main objective of the study was to assess the safety and tolerability of 2 x 1010 CFU LGG administered orally to elderly subjects for 28 days. Secondary objectives were to evaluate the richness and microbial diversity in nasopharyngeal and stool specimens using pyrosequencing, and to compare cytokine production in response to bacterial stimulation by following the kinetics of mRNA expression of pro and anti-inflammatory genes and different signaling pathways, in relation to changes in stool Bifidobacterium and Lactobacillus spp. The study was reviewed and approved by the Partners Human Research Committee (IRB # 2010P001695) and was registered at ClinicalTrials.gov (NCT01274598). The main results regarding the clinical signs and safety of intervention is published in PLoS One. 2014 Dec 1;9(12):e113456. doi: 10.1371/journal.pone.0113456. eCollection 2014. PMID: 25438151. RNA sequencing for transcriptome analysis was only done in 11 of the 15 subjects as RNA integrity and quantity had to be optimal for the three times where blood was collected in order for a subject to be included in the study. The information regarding the microbiome data associated with this study is presented in a separate paper, which can be found at dbGaP study accession, phs000896, and PMID: 25873374.

  Study phs000928

• Plasma DNA profile in DNASE1L3 deficiency-Mouse AAV samples

  Plasma DNA profile in DNASE1L3 deficiency-Mouse AAV

  Study EGAS00001004409

• The Genetic Landscape of Metastasis and Recurrence in Head and Neck Squamous Cell Carcinoma

  Recurrence and/or metastasis occur in more than half of patients with head and neck squamous cell carcinoma (HNSCC) and pose the greatest threats to long-term survival. The genetic alterations underlying recurrent/metastatic HNSCC are unknown. This study represents the first whole exome sequencing (WES) cohort study of patient-matched tumor pairs in recurrent or metastatic HNSCC. Synchronous lymph node metastases are genetically more similar to their paired index primary tumors than metachronous recurrent tumors are. Newly arisen mutations in recurrent or metastatic tumors, may have therapeutic implications. Several genes were found to be mutated in multiple metastatic or recurrent tumors, but not in their respective primaries, including C17orf104, ITPR3, and DDR2. DDR2 mutations have been shown to confer enhanced sensitivity to Src-family kinase (SFK) inhibitors in other malignancies. Similarly, we found HNSCC cell lines harboring endogenous and engineered DDR2 mutations to be more sensitive to the SFK inhibitor dasatinib, than those with WT DDR2. This study outlines the first compendium of somatic mutations in primary, metastatic and/or recurrent HNSCC cancers that arise in individual patients; and demonstrates how such data can be used to interrogate potential predictive/prognostic biomarkers to inform and guide personalized therapy.

  Study phs001007

• Discovery of Non-ETS Gene Fusions in Human Prostate Cancer using Next Generation RNA Sequencing

  Half of prostate cancers harbor gene fusions between TMPRSS2 and members of the ETS transcription factor family. To date little is known about the presence of non-ETS fusion events in prostate cancer. We employed next-generation transcriptome sequencing (RNA-Seq) in order to explore the whole transcriptome of 25 human prostate cancer samples for the presence of chimeric fusion transcripts. We generated more than 1 billion sequence reads and used a novel computational approach (FusionSeq) in order to identify novel gene fusion candidates with high confidence. In total, we discovered and characterized seven new cancer-specific gene fusions, two involving the ETS genes ETV1 and ERG, and five involving non-ETS genes such as CDKN1A (p21), CD9 and IKBKB (IKK-beta), genes known to exhibit key biological roles in cellular homeostasis or assumed to be critical in tumorigenesis of other tumor entities, as well as the oncogene PIGU and the tumor suppressor gene RSRC2. The novel gene fusions are found to be of low frequency but interestingly, the non-ETS fusions were all present in prostate cancer harboring the TMPRSS2-ERG gene fusion. Future work will focus on determining if the ETS rearrangements in prostate cancer are associated or directly predispose to a rearrangement prone phenotype.

  Study phs000310