Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array
Authors
Saunders, Edward J
Dadaev, Tokhir
Leongamornlert, Daniel A
Benlloch, Sara
Giles, Graham G
Wiklund, Fredrik
Grönberg, Henrik
Haiman, Christopher A
Schleutker, Johanna
Nordestgaard, Børge G
Travis, Ruth C
Neal, David
Pasayan, Nora
Stanford, Janet L
Blot, William J
Thibodeau, Stephen N
Maier, Christiane
Kibel, Adam S
Cybulski, Cezary
Cannon-Albright, Lisa
Brenner, Hermann
Park, Jong Y
Kaneva, Radka
Batra, Jyotsna
Teixeira, Manuel R
Pandha, Hardev
Govindasami, Koveela
Muir, Ken
The, UK Genetic Prostate Cancer Study Collaborators
The, UK ProtecT Study Collaborators
The, PRACTICAL Consortium
Eeles, Rosalind A
Kote-Jarai, Zsofia
Publication Date
2016-03-10Journal Title
British Journal of Cancer
ISSN
0007-0920
Publisher
Nature Publishing Group
Volume
114
Pages
945-952
Language
English
Type
Article
Metadata
Show full item recordCitation
Saunders, E. J., Dadaev, T., Leongamornlert, D. A., Amin Al Olama, A., Benlloch, S., Giles, G. G., Wiklund, F., et al. (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, 114 945-952. https://doi.org/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 ~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.
Keywords
DNA repair, prostate cancer, genome-wide association study, GWAS, iCOGS
Sponsorship
MRC (G0500966)
National Cancer Institute (NCI) (R01CA128978)
National Cancer Institute (NCI) (U19CA148537)
MEDICAL RESEARCH COUNCIL (MR/N003284/1)
MRC (G0401527)
MRC (G1000143)
Cancer Research UK (CRUK-A12014)
Cancer Research UK (CRUK-A10118)
Cancer Research UK (A8649)
Embargo Lift Date
2300-01-01
Identifiers
External DOI: https://doi.org/10.1038/bjc.2016.50
This record's URL: https://www.repository.cam.ac.uk/handle/1810/255991
Rights
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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