Primers

Individual disease-associated variants may confer only modest disease risk, but the combined effect of all known associated SNPs on risk can be substantial. Using a combined genetic risk score, these studies show that profiling individuals in the highest and lowest relative risk groups has potential for the development of population-based risk screening and stratification programs. However, further studies are needed to incorporate non-genetic susceptibility factors in these models, as well as validation of these estimates and risk prediction models on additional empirical data sets.

Breast, prostate and ovarian cancers are sometimes grouped together because of the similar effects of estrogen or testosterone exposure on their progression, but little was previously known of their common genetic etiology. COGS found 18 regions containing variants associated with more than 1 of these cancers. For most of these, distinct loci within the same genomic region were identified as associated with different cancers, providing insights into shared mechanisms in the development of these hormone-related cancers.

The COGS project brought together four consortia whose design of the custom iCOGS genotyping array facilitated taking variants from suggestive associations to robust identification in large replication studies. The dense genomic coverage on this array, combined with genotyping across studies for multiple cancers, allowed for the identification of overlapping susceptibility regions suggesting shared mechanisms. The demonstrated benefits of using the iCOGS array have inspired the design of a next-generation cancer genotyping platform to identify risk variants for five of the most prevalent cancers.

The studies from COGS included in this collection nearly double the number of common genetic variants significantly associated with susceptibility to breast, ovarian and prostate cancers. While this set of cancer-associated variants contributes substantially to disease heritability, these studies also predict that an additional large number of common variants not yet associated with disease have the potential to explain the majority of the familial recurrence of these cancers.

It is likely that many of the cancer risk loci found by COGS influence gene regulation, as ~66% of confirmed susceptibility alleles lie within or near genes, with only 5% located within coding regions. Subsequent functional annotation and experimental studies therefore have sought spatial association with transcription factor binding sites, histone modifications or other putative regulatory elements. However, in vitro functional studies in a relevant tissue and cell type, as well as in vivo studies in model organisms, are also needed to provide insight into the mechanisms underlying the development of breast, ovarian and prostate cancers.