Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array

Year: 2016

Type: article

Abstract: BACKGROUND: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B. METHODS: Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes. RESULTS: Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant. CONCLUSIONS: MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.

Source: British Journal of Cancer

DOI: 10.1038/bjc.2016.50

Institutions: Royal Marsden NHS Foundation Trust, Institute of Cancer Research, University of Cambridge, Cancer Council Victoria, Karolinska Institutet, The University of Melbourne, University of Southern California, USC Norris Comprehensive Cancer Center, University of Turku, Herlev Hospital, Copenhagen University Hospital, Gentofte Hospital, University of Oxford, Fimlab (Finland), University of Tampere, Cancer Research UK, Cancer Research UK Cambridge Center, Addenbrooke's Hospital, University College London, University of Washington, Fred Hutch Cancer Center, International Epidemiology Institute, Mayo Clinic, University Hospital Ulm, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Dana-Farber Brigham Cancer Center, International Hereditary Cancer Center, Pomeranian Medical University, University of Utah, George E. Wahlen Department of VA Medical Center, German Cancer Research Center, National Center for Tumor Diseases, Deutsches Konsortium für Translationale Krebsforschung, Moffitt Cancer Center, Medical University of Sofia, Queensland University of Technology, Universidade do Porto, Instituto de Ciências Biomédicas Albel Salazar, University of Surrey, Instituto Português de Oncologia Francisco Gentil, University of Warwick

Language: English

Topic: Genetic Associations and Epidemiology

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $2,970

Funders: Cancer Research UK, National Institute for Health and Care Research, Medical Research Council, National Cancer Institute

OpenAlex ID: W2337895764