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. 2016 Apr 12;114(8):945-52.
doi: 10.1038/bjc.2016.50.

Gene and Pathway Level Analyses of Germline DNA-repair Gene Variants and Prostate Cancer Susceptibility Using the iCOGS-genotyping Array

Collaborators
Free PMC article

Gene and Pathway Level Analyses of Germline DNA-repair Gene Variants and Prostate Cancer Susceptibility Using the iCOGS-genotyping Array

Edward J Saunders et al. Br J Cancer. .
Free PMC article

Erratum in

  • 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, Al 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; UK Genetic Prostate Cancer Study Collaborators; UK ProtecT Study Collaborators; PRACTICAL Consortium, Easton DF, Eeles RA, Kote-Jarai Z. Saunders EJ, et al. Br J Cancer. 2018 Mar 20;118(6):e9. doi: 10.1038/bjc.2017.468. Epub 2018 Feb 13. Br J Cancer. 2018. PMID: 29438362 Free PMC article.

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 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.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Single SNP case–control Manhattan Plot. In total, 81 303 SNPs from 179 DNA-repair genes were analysed for association with PrCa. Only the previously reported association within the RAD51B gene was identified, with suggestive, non-significant association peaks observed at a small number of other loci.
Figure 2
Figure 2
Case–control Manhattan Plots for the 179 DNA-repair genes analysed by SKAT. (A) A significant association was observed for the MSH5 gene using the SKAT-C test that examines the combined effect of common and rare variants. (B) No significant association was detected for any gene under the SKAT-O test that primarily focuses on rare variant association testing.

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