Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array.
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Date
2016-04-12Author
Saunders, EJ
Dadaev, T
Leongamornlert, DA
Al Olama, AA
Benlloch, S
Giles, GG
Wiklund, F
Gronberg, H
Haiman, CA
Schleutker, J
Nordestgaard, BG
Travis, RC
Neal, D
Pasayan, N
Khaw, K-T
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
UK Genetic Prostate Cancer Study Collaborators,
UK ProtecT Study Collaborators,
PRACTICAL Consortium,
Easton, DF
Eeles, RA
Kote-Jarai, Z
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
UK Genetic Prostate Cancer Study Collaborators
UK ProtecT Study Collaborators
PRACTICAL Consortium
Humans
Prostatic Neoplasms
Genetic Predisposition to Disease
DNA Repair Enzymes
Cell Cycle Proteins
DNA-Binding Proteins
BRCA1 Protein
DNA
Risk
Case-Control Studies
Prospective Studies
DNA Repair
Genotype
Germ-Line Mutation
Polymorphism, Single Nucleotide
Genes, BRCA2
Male
Genome-Wide Association Study
Research team
Oncogenetics
Language
eng
Date accepted
2016-02-09
License start date
2016-04
Citation
British journal of cancer, 2016, 114 (8), pp. 945 - 952
Publisher
NATURE PUBLISHING GROUP
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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