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Collection of COGS Papers Describe New Common Variant Contributors to Cancer Risk

NEW YORK (GenomeWeb News) – A set of studies stemming from the Collaborative Oncological Gene-environment Study, or COGS, have roughly doubled the number of common genetic variants implicated in prostate, breast, or ovarian cancer.

Members of the large, international consortium genotyped around 250,000 individuals for the COGS project, aimed at understanding the heritability and genetic risk profiles of the three cancers and their related subtypes.

That information, in turn, is expected to contribute to an improved understanding of the biological processes affected in the cancers and to refined risk prediction models for the diseases. There is also hope that the insights will yield clues to coming up with new or refined treatment regimens.

The team presented findings from COGS in 13 studies out today in five research journals.

In general, these analyses centered on its iCOGS genotyping chip, a custom Illumina iSelect array that included SNPs selected using information from prior studies of prostate cancer, breast cancer, and ovarian cancer.

"The center piece of the COGS project was this single chip, the iCOGS," University of Cambridge researcher Douglas Easton, senior author on the primary COGS breast cancer study in Nature Genetics, said during a telephone press briefing this week.

"We realized that we could study the genetic basis of these cancers more efficiently and more informatively using a single chip rather than [multiple] individual chips," Easton explained. "So we set about to designing a single chip which contains about 200,000 genetic markers that were genotyped, eventually, on about a quarter of a million subjects."

When considering breast cancer, for instance, Easton and his co-authors relied on a meta-analysis of nine prior GWAS — representing more than 22,600 cases and controls of European decent — to track down 29,807 suspicious SNPs for inclusion on the iCOGS array.

By using the iCOGS array to genotype another 45,290 individuals with breast cancer and 41,880 unaffected controls, the team tracked down 41 loci showing genome-wide significant associations with breast cancer. Additional COGS studies uncovered eight more loci that seem to contribute to particular breast cancer subtypes.

"If you add those together with the loci that we knew about before, we now know of 76 common genetic [loci] which are associated with breast cancer risk," Easton noted, explaining that common variants at these sites can help in classifying those at highest breast cancer risk.

In another Nature Genetics study published online today, researchers described almost two-dozen new prostate cancer-associated loci identified through a genome-wide association study of 25,074 individuals with prostate cancer and nearly as many unaffected controls.

Each of the cases and controls was assessed at some 211,155 SNPs using the iCOGS array, they explained, leading to 23 loci with genome-wide significant links to prostate cancer. Of those, 16 sites showed ties to aggressive forms of the disease.

Along with other COGS results, that GWAS brings the tally of prostate cancer-associated loci up to 78 so far.

COGS researchers estimated that individuals carrying the highest burden of risk SNPs — those in the top 1 percent of the known risk distribution spectrum — are around 4.7 times more likely to be diagnosed with prostate cancer than individuals in the general population.

That translates to a jump in lifetime risk from around one in 11 up to around 47 percent, co-first author Rosalind Eeles, a researcher affiliated with the UK's Institute of Cancer Research and the Royal Marsden National Health Service, explained during this week's press briefing.

COGS members dug up several new risk loci for ovarian cancer, too. Five of the ovarian cancer-associated loci were detected through a GWAS involving almost 18,200 women with the disease and more than 26,100 without.

"These samples came from over 40 different studies from around the world," University of Cambridge researcher Paul Pharoah, senior author on the primary COGS ovarian cancer study, told reporters.

The researchers tested these cases and controls at 24,551 SNPs that were included on the iCOGS chip based on patterns found in prior ovarian cancer GWAS in North America and the UK, Pharoah and his co-authors explained in Nature Genetics.

This analysis verified ties between ovarian cancer and two loci with somewhat tenuous associations in past studies. It also pointed to three brand new risk loci, including two sites in the genome that appear to share ties to all of the endometrial ovarian cancer types tested.

A third locus, which was specifically associated with the serous ovarian cancer subtype, coincided with DNA methylation shifts that seem to prompt lower-than-usual expression of a gene called HNF1B.

Findings from that study and an accompanying analyses indicate that the same HNF1B gene is over-expressed in another ovarian cancer subtype, called clear cell epithelial ovarian cancer.

When all 12 of the known risk loci for ovarian cancer are considered as a set, Pharoah noted, individuals in the top 1 percent of the risk distribution appear to have around a 3 percent chance of developing ovarian cancer, which is just shy of twice the lifetime risk reported for the general population.

Other COGS analyses out today included a Nature Genetics study focused on common variants associated with breast cancer risk in women who have estrogen receptor-negative forms of the disease. There, a GWAS involving more than 6,500 women with ER-negative breast cancer and nearly 42,000 unaffected controls unearthed four loci linked to ER-negative breast cancer but not to forms of breast cancer that include estrogen receptor expression.

In a pair of studies published in PLOS Genetics, meanwhile, COGS members searched for additional genetic modifiers of breast and/or ovarian cancer in women carrying risk mutations in the BRCA1 or BRCA2 genes.

In addition to finding the sorts of variants that may improve risk prediction models, COGS members noted that the new analyses are offering clues about how many prostate or breast cancer risk variants remain undetected in the genome. For breast cancer, for instance, COGS researchers estimate that there are around 1,000 risk SNPs yet to be found. The number of undetected variants coinciding with prostate cancer risk is believed to be about double that.

Findings from the COGS effort are being presented online through a Nature Genetics website housing a collection of research articles and related essays and perspectives articles.