Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer

Abstract

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.

Genome-wide association study identifies new susceptibility loci for epithelial ovarian cancer in Han Chinese women

“…In addition to familial BRCA1 and BRCA2 mutations, there are other kinds of genetic risk factors, including common genetic variants of lower penetrance 2,3 . Molecular epidemiological studies have been conducted with the candidate gene approach to identify low penetrance susceptibility genes for ovarian cancer, many of which have showed inconsistent results [4][5][6][7][8][9][10][11] . Recent genome-wide association studies (GWASs) have reported 11 new singlenucleotide polymorphisms (SNPs) that are associated with ovarian cancer risk in European populations [12][13][14][15][16][17] .…”

Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer

“…Based on data from the Cancer Genome Atlas, homologous deletion of AKTIP occurs in multiple cancer lineages including breast (2%), ovary (0.9%), and prostate (1%), consistent with a tumor-suppressor role. However, the functional role of AKTIP could be tumor type-specific, since it has been proposed as a putative oncoprotein in cervical cancer but a tumor suppressor in ovarian cancer (Cinghu et al 2011;Notaridou et al 2011). INHBA encodes inhibin beta A, a subunit of both the activin and inhibin receptors of the transforming growth factor (TGF-beta) superfamily (Risbridger et al 2001).…”

Molecular genetics and epidemiology of epithelial ovarian cancer (Review)

“…1). Studies published in Finland (43) and Denmark (10) in the past several decades suggest rates comparable to the United States. Among white women, the reported incidence rates for invasive SAC, EAC, and CCC increased during 1978-1998 (44).…”