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Researchers ID Breast Cancer Risk Variants in BRCA2 Mutation Carriers

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A new genetic study has uncovered variants associated with overall breast cancer risk that apparently modify the degree of breast cancer risk conferred by BRCA2 mutations.

By genotyping thousands of BRCA2 mutation carriers with or without breast cancer, a large, international research team not only identified common variants associated with breast cancer overall, but also found variants that affect the relative risk of breast cancer in individuals with BRCA2 mutations. Based on their findings, those involved in the study say variants that moderate BRCA2-related breast cancer risk appear to overlap with those implicated in other breast cancers. The study appeared online last night in PLoS Genetics.

"In this GWAS of BRCA2 mutation carriers, the first in this high risk population, we found previously identified breast cancer susceptibility loci modified risk of BRCA2-associate breast cancer with similar magnitude of association," corresponding author Kenneth Offit, a medical oncologist with Memorial Sloan-Kettering Cancer Center's Clinical Genetics Service, and co-authors wrote.

Mutations affecting the BRCA1 and BRCA2 genes are known to increase an individual's risk of breast and other cancers, the researchers explained. But the level of risk is not the same for all individuals with inherited mutations in these genes, they added, and questions remain about what sorts of additional genetic changes dial this risk up or down.

In an online paper in Nature Genetics last month, an international research group including Offit and other members of the team reported on BRCA1-related breast risk modifiers they identified using a GWAS approach.

For the latest study, the researchers focused on variants moderating breast cancer risk associated with inherited changes in BRCA2, which appear to have a particularly broad range of penetrance patterns.

"The risk of breast cancer associated with BRCA2 mutations varies widely," Offit said in a statement. "Our goal in this study was to test the hypothesis that common genetic variants may modify cancer risk in those already carrying 'high risk' mutations."

To do this, the team first genotyped more than 1,700 BRCA2 mutation carriers who were of European descent and under the age of 40 years old using the Affymetrix Genome-Wide Human SNP 6.0 array. Within this group, 899 women had been diagnosed with breast cancer, while 804 had not.

Individuals included in the study had been recruited through several international studies, including the Consortium for Investigators of Modifiers of BRCA1/2.

Using data from the original cohort as well as genotyping data for another 1,264 BRCA2 mutation carriers diagnosed with cancer and 1,222 unaffected carriers, the researchers found four SNPs in particular that seemed to increase breast cancer risk.

These included SNPs in FGFR2 and TOX3 that had been previously linked to breast cancer, as well as variants in the chromosome 10 gene ZNF365 and on chromosome 20, near the GMEB2, SRMS, PTK6, STMN3, and TNFRSF6 genes.

The researchers also looked for variants altering the relative risk associated with BRCA2 mutations. But rather than finding a set of variants distinct from those found in non-BRCA2-related breast cancer, they explained, "only those loci known to be associated with breast cancer risk in the general population, including FGFR2, modified BRCA2-associated risk in our high-risk population."

Based on their findings so far, the team argued that it's unlikely that there are other undetected common variants with a strong influence over BRCA2 penetrance. And while they conceded that more rare variants not assessed in the study may also be involved in moderating BRCA2-related breast cancer risk, the researchers explained that identifying such changes "would require study populations much larger than the current analysis, which is presently the largest such cohort assembled."