title: Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer.
abstract: Low-moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in approximately 1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P(dominant)=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case-control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80-0.99) and remained statistically significant (P(dominant)=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P(global)=0.034) and a haplotype in BRAF that had a protective effect (P(global)=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC.
authors.affiliation: Gynaecological Oncology Department, UCL EGA Institute for Women's Health, University College London, London, UK.
authors.forename: L
authors.initials: L
authors.lastname: Quaye
authors.forename: H
authors.initials: H
authors.lastname: Song
authors.forename: S J
authors.initials: SJ
authors.lastname: Ramus
authors.forename: A
authors.initials: A
authors.lastname: Gentry-Maharaj
authors.forename: E
authors.initials: E
authors.lastname: Høgdall
authors.forename: R A
authors.initials: RA
authors.lastname: DiCioccio
authors.forename: V
authors.initials: V
authors.lastname: McGuire
authors.forename: A H
authors.initials: AH
authors.lastname: Wu
authors.forename: D J
authors.initials: DJ
authors.lastname: Van Den Berg
authors.forename: M C
authors.initials: MC
authors.lastname: Pike
authors.forename: E
authors.initials: E
authors.lastname: Wozniak
authors.forename: J A
authors.initials: JA
authors.lastname: Doherty
authors.forename: M A
authors.initials: MA
authors.lastname: Rossing
authors.forename: R B
authors.initials: RB
authors.lastname: Ness
authors.forename: K B
authors.initials: KB
authors.lastname: Moysich
authors.forename: C
authors.initials: C
authors.lastname: Høgdall
authors.forename: J
authors.initials: J
authors.lastname: Blaakaer
authors.forename: D F
authors.initials: DF
authors.lastname: Easton
authors.forename: B A J
authors.initials: BA
authors.lastname: Ponder
authors.forename: I J
authors.initials: IJ
authors.lastname: Jacobs
authors.forename: U
authors.initials: U
authors.lastname: Menon
authors.forename: A S
authors.initials: AS
authors.lastname: Whittemore
authors.forename: S
authors.initials: S
authors.lastname: Krüger-Kjaer
authors.forename: C L
authors.initials: CL
authors.lastname: Pearce
authors.forename: P D P
authors.initials: PD
authors.lastname: Pharoah
authors.forename: S A
authors.initials: SA
authors.lastname: Gayther
mesh_terms: D000328:Adult; D000368:Aged; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D018734:Genes, erbB-2; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008875:Middle Aged; D009857:Oncogenes; D010051:Ovarian Neoplasms / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C117307:KRAS protein, human; C099927:NMI protein, human; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins