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

Saunders, EJ, Dadaev, T, Leongamornlert, DA, Olama, AA, Benlloch, S, Giles, GG, Wiklund, F, Grönberg, H, Haiman, CA, Schleutker, J , Nordestgaard, BG, Travis, RC, Neal, D, Pasayan, N, Khaw, KT, Stanford, JL, Blot, WJ, Thibodeau, SN, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, JY, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Govindasami, K, Muir, K, Genetic Prostate Cancer Study Collaborators, UK, ProtecT Study Collaborators, UK, Consortium, PRACTICAL, Easton, DF, Eeles, RA and Kote-Jarai, Z (2016) 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. pp. 945-952.

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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 ∼100 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 Type: Article
Subjects : Medical Science
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Saunders, EJ
Dadaev, T
Leongamornlert, DA
Olama, AA
Benlloch, S
Giles, GG
Wiklund, F
Grönberg, H
Haiman, CA
Schleutker, J
Nordestgaard, BG
Travis, RC
Neal, D
Pasayan, N
Khaw, KT
Stanford, JL
Blot, WJ
Thibodeau, SN
Maier, C
Kibel, AS
Cybulski, C
Cannon-Albright, L
Brenner, H
Park, JY
Kaneva, R
Batra, J
Teixeira, MR
Pandha, H
Govindasami, K
Muir, K
Genetic Prostate Cancer Study Collaborators, UK
ProtecT Study Collaborators, UK
Consortium, PRACTICAL
Easton, DF
Eeles, RA
Kote-Jarai, Z
Date : 10 March 2016
Identification Number : 10.1038/bjc.2016.50
Copyright Disclaimer : © 2016 Cancer Research UK. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Depositing User : Symplectic Elements
Date Deposited : 13 Sep 2016 08:59
Last Modified : 31 Oct 2017 18:41
URI: http://epubs.surrey.ac.uk/id/eprint/812123

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