1. Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.
- Author
-
Pearce CL, Near AM, Van Den Berg DJ, Ramus SJ, Gentry-Maharaj A, Menon U, Gayther SA, Anderson AR, Edlund CK, Wu AH, Chen X, Beesley J, Webb PM, Holt SK, Chen C, Doherty JA, Rossing MA, Whittemore AS, McGuire V, DiCioccio RA, Goodman MT, Lurie G, Carney ME, Wilkens LR, Ness RB, Moysich KB, Edwards R, Jennison E, Kjaer SK, Hogdall E, Hogdall CK, Goode EL, Sellers TA, Vierkant RA, Cunningham JM, Schildkraut JM, Berchuck A, Moorman PG, Iversen ES, Cramer DW, Terry KL, Vitonis AF, Titus-Ernstoff L, Song H, Pharoah PD, Spurdle AB, Anton-Culver H, Ziogas A, Brewster W, Galitovskiy V, and Chenevix-Trench G
- Subjects
- Adult, Aged, Case-Control Studies, Cohort Studies, DNA Ligase ATP, Female, Genotype, Heterozygote, Homozygote, Humans, Middle Aged, Neoplasm Invasiveness, Ovarian Neoplasms pathology, Risk Factors, Cytochrome P-450 CYP3A genetics, DNA Ligases genetics, DNA-Binding Proteins genetics, Genetic Predisposition to Disease, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide genetics
- Abstract
The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.
- Published
- 2009
- Full Text
- View/download PDF