The inherited genetics of ovarian and endometrial cancer

Abstract

Endometrial and epithelial ovarian cancers are the fourth and fifth most common cancers in women in developed countries, after breast, lung, and colorectal cancer. In the United States alone, in 2008 there were about 40,000 new diagnoses of endometrial cancer and 7500 disease-related deaths. For ovarian cancer, there were about 22,000 new diagnoses and 15,000 deaths over the same period. The purpose of this article is to review the recent developments in the inherited genetics of ovarian and endometrial cancer, with particular attention to recent progress in identifying common low-penetrance susceptibility genes and their clinical implications.

Figure 1

Genome-wide association study (GWAS) design applied to epithelial ovarian cancer to identify common low-moderate susceptibility alleles for the disease. (a) As with many other genome-wide association studies, a staged study design was used in the first published GWAS for ovarian cancer [38^••]. Here, a large number of SNPs are genotyped in a restricted number of subjects in a first stage, followed by statistical sieving to identify a proportion of putative associated SNPs. These SNPs then undergo validation in a larger series of subjects in stage 2 followed by more stringent statistical selection to identify a limited number of SNPs for further validation in additional cases and controls in stage 3. (b) Details of the ovarian cancer GWAS, which has so far included approximately 11 000 invasive epithelial ovarian cancer cases and more than 13 000 unaffected controls from 29 different ovarian cancer studies that are part of the International Ovarian Cancer Association Consortium (OCAC) ([38^••] and unpublished data). (c) A Manhattan plot illustrating the genotyping data in a combined stage 1 and stage 2 analysis of more than 22 000 SNPs, according to statistical significance (p-value). Red spots indicate the most significant SNPs at p < 10⁻⁵; note the series of correlated, statistically significant SNPs at the 9p22 locus, suggesting the location of the first common susceptibility locus identified for ovarian cancer [38^••].

Figure 2

Analysis of SNPs genotyped for the six most significant ovarian cancer susceptibility loci after stratifying cases according to the four main histological subtypes (serous, mucinous, endometrioid and clear cell). These data suggest substantial genetic heterogeneity. The strength of association is stronger in serous-only ovarian cancer cases compared to all other subtypes for five of the six loci. For the 8q24 and 19p13 loci, the effects appear to be specific to the serous subtype without any evidence of association for other subtypes. The only locus that shows evidence of association for additional subtypes is the 2q31 locus; the data suggest risk associations in mucinous and endometrioid ovarian cancer cases, as well as the serous subtype ([38^••] and unpublished data).