title: Gene and pathway level analyses of  germline DNA-repair gene variants and  prostate cancer susceptibility using the  iCOGS-genotyping array.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Saunders
authors.forename: Tokhir
authors.initials: T
authors.lastname: Dadaev
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Leongamornlert
authors.forename: Ali Amin
authors.initials: AA
authors.lastname: Al Olama
authors.forename: Sara
authors.initials: S
authors.lastname: Benlloch
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wiklund
authors.forename: Henrik
authors.initials: H
authors.lastname: Gronberg
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.forename: Johanna
authors.initials: J
authors.lastname: Schleutker
authors.forename: Borge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Travis
authors.forename: David
authors.initials: D
authors.lastname: Neal
authors.forename: Nora
authors.initials: N
authors.lastname: Pasayan
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stanford
authors.forename: William J
authors.initials: WJ
authors.lastname: Blot
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Christiane
authors.initials: C
authors.lastname: Maier
authors.forename: Adam S
authors.initials: AS
authors.lastname: Kibel
authors.forename: Cezary
authors.initials: C
authors.lastname: Cybulski
authors.forename: Lisa
authors.initials: L
authors.lastname: Cannon-Albright
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.forename: Jong Y
authors.initials: JY
authors.lastname: Park
authors.forename: Radka
authors.initials: R
authors.lastname: Kaneva
authors.forename: Jyotsna
authors.initials: J
authors.lastname: Batra
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
authors.forename: Hardev
authors.initials: H
authors.lastname: Pandha
authors.forename: Koveela
authors.initials: K
authors.lastname: Govindasami
authors.forename: Ken
authors.initials: K
authors.lastname: Muir
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Eeles
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Kote-Jarai
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics; D004247:DNA / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D024522:Genes, BRCA2 / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000235:genetics*; D012306:Risk
chemical_list: D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C118481:MSH5 protein, human; C513287:RAD23B protein, human; C413002:RAD51B protein, human; D004247:DNA; D045643:DNA Repair Enzymes