Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain
the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in
Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles
Nature Genetics is pleased to present the iCOGS Focus comprising a collection of 13 papers from COGS, representing a significant advance in our understanding of genetic susceptibility to three hormone-related cancers: breast, ovarian and prostate cancer. We hope that you will find this Focus issue, as well as the accompanying Focus online, a useful guide to this milestone in genetic epidemiology.
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.
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.
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.
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.
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.
Douglas Easton, Per Hall and colleagues report meta-analyses of genome-wide association studies for breast cancer, including 10,052 cases and 12,575 controls, followed by genotyping using the iCOGS array in an additional 52,675 cases and 49,436 controls from studies within the Breast Cancer Association Consortium (BCAC). They identify 41 loci newly associated with susceptibility to breast cancer.
Rosalind Eeles and colleagues report meta-analysis of genome-wide association studies for prostate cancer and genotyping on the custom iCOGS array in 25,074 cases and 24,272 controls from 32 studies available in the PRACTICAL Consortium. They identify 23 new prostate cancer susceptibility loci, 20 of which are associated with both aggressive and non-aggressive disease.
Paul Pharoah, Joellen Schildkraut, Thomas Sellers and colleagues report a meta-analysis of genome-wide association studies for epithelial ovarian cancer and genotyping using the iCOGS array in 18,174 cases and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. They identify three new ovarian cancer susceptibility loci, including one specific to the serous subtype, and their integrated molecular analysis of genes and regulatory regions at these loci suggests disease mechanisms.
Montserrat Garcia-Closas and colleagues report a meta-analysis of three genome-wide association studies for estrogen receptor (ER)-negative breast cancer, including 4,193 ER-negative breast cancer cases and 35,194 controls, with replication using the iCOGS custom genotyping array in 40 studies, including 6,514 cases and 41,455 controls. They identify four loci associated with ER-negative but not ER-positive breast cancer.
Stig Bojesen, Georgia Chenevix-Trench, Alison Dunning and colleagues report common variants at the TERT-CLPTM1L locus associated with mean telomere length measured in whole blood. They also identify associations at this locus to breast or ovarian cancer susceptibility and report functional studies in breast and ovarian cancer tissue and cell lines.