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

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Saunders, EJ and Dadaev, T and Leongamornlert, DA and Al Olama, AA and Benlloch, S and Giles, GG and Wiklund, F and Gronberg, H and Haiman, CA and Schleutker, J and Nordestgaard, BG and Travis, RC and Neal, D and Pasayan, N and Khaw, KT and Stanford, JL and Blot, WJ and Thibodeau, SN and Maier, C and Kibel, AS and Cybulski, C and Cannon-Albright, L and Brenner, H and Park, JY and Kaneva, R and Batra, J and Teixeira, MR and Pandha, H and Govindasami, K and Muir, K and Easton, DF and Eeles, RA and Kote-Jarai, Z and Fitzgerald, LM and The UK Genetic Prostate Cancer Study Collaborators, The UK ProtecT Study Collaborators, The PRACTICAL Consortium, Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array, British Journal of Cancer, 114, (8) pp. 945-952. ISSN 0007-0920 (2016) [Refereed Article]


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Copyright 2016 Cancer Research UK. All rights reserved. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) http://creativecommons.org/licenses/by/4.0/

DOI: doi:10.1038/bjc.2016.50

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.

Item Details

Item Type:Refereed Article
Keywords:prostate cancer, GWAS, DNA repair
Research Division:Medical and Health Sciences
Research Group:Oncology and Carcinogenesis
Research Field:Cancer Genetics
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Cancer and Related Disorders
UTAS Author:Fitzgerald, LM (Dr Liesel Fitzgerald)
ID Code:118280
Year Published:2016
Web of Science® Times Cited:11
Deposited By:Menzies Institute for Medical Research
Deposited On:2017-07-10
Last Modified:2017-11-06
Downloads:74 View Download Statistics

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