A comprehensive genetic analysis of common cancer risk through the development of the Oncochip. C. I. Amos1, A. C. Antoniou2, A. Berchuck3, G. Chenevix-Trench4, F. J. Couch5, R. A. Eeles6, L. J. Esserman7, S. A. Gayther8, C. L. Goh6, D. E. Goldgar9, S. B. Gruber8, C. A. Haiman8, P. Hall10, D. J. Hunter11, Z. Kote-Jarai6, P. K. Lepage12, S. Lindstrom11, J. McKay13, R. L. Milne14, U. Peters15, P. D. Pharoah2, C. M. Phelan16, F. R. Schumacher8, T. A. Sellers16, J. Simard17, Z. Wang12, D. Seminara12, S. J. Chanock12, D. F. Easton2, B. E. Henderson8 1) Community and Family Medicine, Geisel School of Medicine at Dartmouth, Lebanon, NH; 2) University of Cambridge, Cambridge, UK; 3) Duke University, Durham, NC; 4) The Queensland Institute of Medical Research, Herston, Australia; 5) Mayo Clinic, Rochester, MN; 6) The Institute of Cancer Research, Sutton, UK; 7) University of California, San Francisco, CA; 8) University of Southern California, Los Angeles, CA; 9) University of Utah, Salt Lake City, UT; 10) Karolinska Institutet, Stockholm, Sweden; 11) Harvard School of Public Health, Boston, MA; 12) National Cancer Institute, Bethesda, MD; 13) International Agency for Research on Cancer, Lyon, France; 14) Spanish National Cancer Research Centre, Madrid, Spain; 15) Fred Hutchinson Cancer Research Insitute, Seattle, WA; 16) Moffitt Cancer Center, Tampa, FL; 17) CHU de Québec Research Center, Québec, Canada.

   Identifying the genetic determinants of complex diseases through genome-wide association studies (GWAS) has been hampered by application of variety of different genotyping platforms, on often limited collections of cases and controls. In particular, evaluating the role that cancer subtype heterogeneity, gene-gene and gene-environment interactions have upon cancer susceptibility and subsequent risk profiling requires large data sets. To facilitate a more comprehensive evaluation of susceptibility to common cancers we formed a consortium comprising investigators from the Genetic Associations and Mechanisms of Oncology (GAME-ON), Personalised Risk Stratification for Prevention and Early Detection of Breast Cancer, The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL), the Breast Cancer Case Control Consortium (BCAC), the Breast and Prostate Cancer Cohort Consortium (BPC3), Ovarian Cancer case control consortium (OCAC) and ATHENA Breast Health Network and the NIEHS Sisters studies. By bringing together multiple consortia, we have been able to design a custom Illumina array that incorporates approximately 600,000 markers and which will be genotyped on at least 400,000 samples, including patients affected with breast, prostate, ovarian, lung and colon cancers, respective controls, and individuals with BRCA1 or BRCA2 mutations. The array incorporates fine-scale mapping of more than 150 known cancer susceptibility regions, variants showing evidence for association from previous GWAS, putative risk variants identified through exome or whole genome sequencing, and other functional candidate variants potentially associated with disease risk. The array will include a backbone of 260K markers selected for high genome-wide coverage of common variants based on the 1000 genomes project, providing the basis for discovery of new associations for any cancer or associated trait. Additionally we selected markers associated with pharmacological outcomes, gene expression in multiple tissues, and traits (e.g. smoking behavior, menarche, BMI) that are associated with cancer risk. When completed, this analysis will be one of the largest conducted using a common custom genotyping array, and will allow comprehensive evaluation of the genetic architecture of multiple common cancer types.

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