In genome-wide association studies, the bigger, the better—this week, a mega-consortium has published the results from the biggest cancer genotyping effort to date.
Thirteen papers, based on genetic data from 200,000 individuals, are being published today (March 27) in Nature Genetics, Human Molecular Genetics, Nature Communications, PLoS Genetics, and The American Journal of Human Genetics. The papers report 74 new genetic variants, or single nucleotide polymorphisms (SNPs), associated with three hormone-related cancers: breast, prostate, and ovarian cancer.
“These 13 papers represent a milestone in our understanding of these common cancers,” said Orli Bahcall, senior Nature Genetics editor who led the publication of the collection, at a press briefing on Monday. The new SNPs help explain up to one-third of the inherited risk for each cancer type, she said, and common SNPs identified among the cancer types point to shared mechanisms or pathways in hormone-related cancers.
The findings could lead to genetic cancer screening programs that include the newly identified SNPs, according to Douglas Easton of the University of Cambridge, who led several of the studies. But “it will take some time before it becomes widespread,” he said.
The studies are all part of the Collaborative Oncological Gene-environment Study (COGS), an EU-funded consortium designed to improve understanding of genetic susceptibility to the three hormone-related cancers. At the center of the COGS project is a custom genotyping array, called iCOGs, made by Illumina, Inc. and composed of 211,155 SNPs chosen from past GWAS studies or traits linked to cancer risk. “We realized that we could study the genetic basis of these cancers more efficiently and more informatively using a single chip rather than individual chips,” said Easton. The iCOGs chip includes 29,807 SNPs linked to breast cancer, 24,551 associated with ovarian cancer and 85,278 relevant to prostate cancer.
At the heart of the COGs publications are three key papers in Nature Genetics, detailing most of the new SNPs:
- In a study of 40,000 breast cancer patients and 40,000 controls, Easton’s team identified 41 new SNPs clearly associated with breast cancer risk (1). Two other papers from the group identified an additional 8 SNPs associated with breast cancer, raising the total new variants for breast cancer to 49 (2, 3). Added to previously known loci, researchers now know of 76 SNPs associated with breast cancer risk, which explain about 50 percent of the heritability of breast cancer.
- In a study of 18,000 ovarian cancer patients and 26,000 healthy controls, Paul Pharoah at the University of Cambridge and colleagues pinpointed 5 new markers associated with ovarian cancer risk (4). Those 5 plus 3 additional markers described in other COGS papers and 4 previously known markers make a total of 12 SNPs for ovarian cancer risk. These 12 SNPs explain 40 percent of the heritability of ovarian cancer.
- Finally, in a study of 25,000 prostate cancer cases compared to 25,000 controls, Rosalind A. Eeles at the The Institute of Cancer Research and colleagues identified 23 new prostate cancer SNPs of significance, 16 of which are associated with aggressive disease (5). Seventy-eight prostate cancer susceptibility SNPs have now been identified, and these genetic variants explain 36 percent of the familial risk for the disease.
The total known SNPs, including those newly identified, explain roughly 35-50 percent of the heritability of each disease, as noted above, but that leaves over 50 percent of the heritability unexplained. This is likely due to additional SNPs that haven’t yet been identified, including rare variants, said Easton. For example, in breast cancer 76 SNPs have now been identified, but “there are probably several thousand of these, at least,” he said. Discovering those unknown SNPs will likely require both more analysis of the current data and larger genome-wide association studies in the future, he added.
For more on the COGs papers, check out a website devoted to the collection (www.nature.com/icogs), including interactive guides to lead readers though the studies and findings.
1. Michailidou, K., et al. 2013. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet., doi:10.1038/ng.2563.
2. Garcia-Closas, M., et al. 2013. Genome-wide association studies identify four ER negative–specific breast cancer risk loci. Nat Genet., doi:10.1038/ng.2561.
3. Bojesen, S.E., et al. 2013. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nat Genet., doi:10.1038/ng.2566.
4. Pharoah, P.D., et al. 2013. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer. Nat Genet., doi:10.1038/ng.2564.
5. Eeles, R.A., et al. 2013. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nat Genet., doi:10.1038/ng.2560.