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Meta-Analysis Yields New Breast Cancer Risk Loci

NEW YORK (GenomeWeb) – A genome-wide association study meta-analysis appearing online today in Nature Genetics describes more than a dozen new loci with apparent ties to breast cancer risk in European women.

An international team led by investigators at the University of Cambridge brought together data for around 100,000 women with or without breast cancer, including tens of thousands who'd been genotyped with the custom iCOGS array. The search led to breast cancer-associated variants at more than 70 sites implicated in the disease in the past as well as 15 new loci.

"As well as giving us more information about how and why a higher breast cancer risk can be inherited, the genetic markers we found can help us to target screening and cancer prevention measures at those women who need them the most," corresponding author Douglas Easton, a genetic epidemiology researcher at the University of Cambridge, and colleagues wrote.

"The next bit of solving the puzzle involves research to understand more about how genetic variations work to increase a woman's risk," Easton said. "And we're sure there are more of these variations still to be discovered."

Previous studies have unearthed a handful of rare variants associated with medium to high risk of breast cancer, along with dozens of common SNPs that each make a more modest, cumulative contribution to the condition. But despite the progress that's been made, there are still large gaps in understanding the heritability of breast cancer risk, the authors of the new analysis explained.

In an effort to close some of the remaining gaps, the researchers considered data for 15,748 women of European ancestry with breast cancer and 18,084 without — all enrolled through prior genome-wide association studies.

They also folded in data for another 46,786 breast cancer cases and 42,892 unaffected controls genotyped at a set of more than 211,000 SNPs interrogated by the iCOGS array, which was developed studying breast, ovarian, and prostate cancers.

Once the team imputed information from the 1000 Genomes Project, it was able to compare patterns at more than 11 million SNPs in the breast cancer group relative to the unaffected controls — an analysis that ultimately highlighted variants at 15 loci not linked to breast cancer previously.

Because associated SNPs at a dozen of these sites involved variants not directly genotyped by the iCOGS array, researchers attempted to further verify their findings through further testing on thousands of the samples.

They also delved more deeply into potential causal SNPs at the new sites, using enhancer element profiles of mammary cells that were produced for the ENCODE project and potential expression quantitative trait locus patterns teased out of data generated for the Cancer Genome Atlas.

Together, the newly described loci appear to explain around 2 percent of the familial risk of breast cancer, Easton and his co-authors noted, while the complete collection of common variants associated with breast cancer — falling at 90 or so loci — seem to contribute around 16 percent to its heritability. 

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