Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer.
Common germline genetic variation in the population is associated with susceptibility to epithelial ovarian cancer. Microcell-mediated chromosome transfer and expression microarray analysis identified nine genes associated with functional suppression of tumorogenicity in ovarian cancer cell lines; AIFM2, AKTIP, AXIN2, CASP5, FILIP1L, RBBP8, RGC32, RUVBL1 and STAG3. Sixty-three tagging single nucleotide polymorphisms (tSNPs) in these genes were genotyped in 1,799 invasive ovarian cancer cases and 3,045 controls to look for associations with disease risk. Two SNPs in RUVBL1, rs13063604 and rs7650365, were associated with increased risk of serous ovarian cancer [HetOR = 1.42 (1.15-1.74) and the HomOR = 1.63 (1.10-1.42), p-trend = 0.0002] and [HetOR = 0.97 (0.80-1.17), HomOR = 0.74 (0.58-0.93), p-trend = 0.009], respectively. We genotyped rs13063604 and rs7650365 in an additional 4,590 cases and 6,031 controls from ten sites from the United States, Europe and Australia; however, neither SNP was significant in Stage 2. We also evaluated the potential role of tSNPs in these nine genes in ovarian cancer development by testing for allele-specific loss of heterozygosity (LOH) in 286 primary ovarian tumours. We found frequent LOH for tSNPs in AXIN2, AKTIP and RGC32 (64, 46 and 34%, respectively) and one SNP, rs1637001, in STAG3 showed significant allele-specific LOH with loss of the common allele in 94% of informative tumours (p = 0.015). Array comparative genomic hybridisation indicated that this nonrandom allelic imbalance was due to amplification of the rare allele. In conclusion, we show evidence for the involvement of a common allele of STAG3 in the development of epithelial ovarian cancer.
Notaridou, M; Quaye, L; Dafou, D; Jones, C; Song, H; Høgdall, E; Kjaer, SK; Christensen, L; Høgdall, C; Blaakaer, J; McGuire, V; Wu, AH; Van Den Berg, DJ; Pike, MC; Gentry-Maharaj, A; Wozniak, E; Sher, T; Jacobs, IJ; Tyrer, J; Schildkraut, JM; Moorman, PG; Iversen, ES; Jakubowska, A; Mędrek, K; Lubiński, J; Ness, RB; Moysich, KB; Lurie, G; Wilkens, LR; Carney, ME; Wang-Gohrke, S; Doherty, JA; Rossing, MA; Beckmann, MW; Thiel, FC; Ekici, AB; Chen, X; Beesley, J; Australian Ovarian Cancer Study Group/Australian Cancer Study (Ovarian Cancer), ; Gronwald, J; Fasching, PA; Chang-Claude, J; Goodman, MT; Chenevix-Trench, G; Berchuck, A; Pearce, CL; Whittemore, AS; Menon, U; Pharoah, PDP; Gayther, SA; Ramus, SJ; Ovarian Cancer Association Consortium,
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