A1 Refereed original research article in a scientific journal
Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array
Authors: Edward J Saunders, Tokhir Dadaev, Daniel A Leongamornlert, Ali Amin Al Olama, Sara Benlloch, Graham G Giles, Fredrik Wiklund, Henrik Grönberg, Christopher A Haiman, Johanna Schleutker, Børge G Nordestgaard, Ruth C Travis, David Neal, Nora Pasayan, Kay-Tee Khaw, Janet L Stanford, William J Blot, Stephen N Thibodeau, Christiane Maier, Adam S Kibel, Cezary Cybulski, Lisa Cannon-Albright, Hermann Brenner, Jong Y Park, Radka Kaneva, Jyotsna Batra, Manuel R Teixeira, Hardev Pandha, Koveela Govindasami, Ken Muir, The UK Genetic Prostate Cancer Study Collaborators, The UK ProtecT Study Collaborators, The PRACTICAL Consortium, Douglas F Easton, Rosalind A Eeles, Zsofia Kote-Jarai
Publisher: NATURE PUBLISHING GROUP
Publication year: 2016
Journal: British Journal of Cancer
Journal name in source: BRITISH JOURNAL OF CANCER
Journal acronym: BRIT J CANCER
Volume: 114
Issue: 8
First page : 945
Last page: 952
Number of pages: 8
ISSN: 0007-0920
eISSN: 1532-1827
DOI: https://doi.org/10.1038/bjc.2016.50
Web address : http://www.nature.com/bjc/journal/v114/n8/full/bjc201650a.html
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 similar to 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.
