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

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. KibelCezary Cybulski, Lisa Cannon-Albright, Hermann Brenner, Jong Y. Park, Radka Kaneva, Jyotsna Batra, Manuel R. Teixeira, Hardev Pandha, Koveela Govindasami, Ken Muir, Douglas F. Easton, Rosalind A. Eeles, Zsofia Kote-Jarai

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)945-952
Number of pages8
JournalBritish journal of cancer
Volume114
Issue number8
DOIs
StatePublished - Apr 12 2016

Keywords

  • DNA repair
  • GWAS
  • genome-wide association study
  • iCOGS
  • prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Saunders, E. J., Dadaev, T., Leongamornlert, D. A., Al Olama, A. A., Benlloch, S., Giles, G. G., Wiklund, F., Grönberg, H., Haiman, C. A., Schleutker, J., Nordestgaard, BØ. G., Travis, R. C., Neal, D., Pasayan, N., Khaw, K. T., Stanford, J. L., Blot, W. J., Thibodeau, S. N., Maier, C., ... 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(8), 945-952. https://doi.org/10.1038/bjc.2016.50