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International Team Tracks Down Variants Modifying BRCA1-Related Breast Cancer Risk

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – In a paper appearing in the early, online edition of Nature Genetics yesterday, a large, international research group reported that it has identified a genetic locus that modifies BRCA1-related breast cancer risk — a finding that may further improve breast cancer risk prediction in individuals carrying BRCA1 mutations.

"These findings should be useful in helping determine individual risk for breast cancer in BRCA1 carriers," senior author Fergus Couch, a medicine and pathology researcher at the Mayo Clinic in Rochester, Minnesota, said in a statement.

Couch and his colleagues genotyped thousands of individuals carrying BRCA1 mutations, comparing genetic patterns in those who had been diagnosed with breast cancer with those who had not. In the process, they found a handful of chromosome 19 SNPs that seemed to either increase or decrease the degree of breast cancer risk associated with BRCA1 mutations in the discovery and validation groups.

Moreover, by assessing thousands more breast cancer cases and healthy controls, the researchers determined that the same chromosome 19 variants frequently coincide with estrogen negative breast cancers.

A slew of past studies have shown that individuals carrying BRCA1 and/or BRCA2 mutations are at elevated risk of breast and ovarian cancers. But, researchers explained, the extent of cancer risk associated with such mutations can vary depending on an individual's family history.

And though a few of genetic variants modifying BRCA2 associated breast cancer risk have been identified, they added, just two such variants were previously detected for BRCA1, suggesting different genetic factors might influence the extent of BRCA1 and BRCA2-associated breast cancer risk.

For the current study, Couch and his co-workers decided to look for new variants modifying BRCA1-related breast cancer risk, using the Illumina Infinium 610K array to genotype 2,500 individuals recruited through 20 different centers in almost a dozen countries.

All of the participants carried BRCA1 mutations. Half had been diagnosed with invasive breast cancer when they were less than 40 years old and the other half carried BRCA1 risk mutations but had not been diagnosed with breast cancer before the age of 35.

After their quality control steps, the researchers were left with data at more than a half a million SNPs each for 1,193 individuals with cancer and 1,190 without.

When they tested the top 96 SNPs from this study in another set of BRCA1 mutation carriers — including 2,974 individuals who'd been diagnosed with breast cancer and 3,012 who had not — the researchers pinned down five SNPs in a region of chromosome 19 known as 19p13 that were linked to changes in BRCA1-associated breast cancer risk.

Of these, two were associated with elevated breast cancer risk, while three appeared to slightly decrease the breast cancer risk linked to BRCA1 mutations, the researchers explained. Even so, they added, data so far suggests the variants don't modify BRCA1-related ovarian cancer risk.

In their follow-up analyses, the team began parsing the SNPs most closely related to certain types of BRCA1 mutations and also looked at how breast cancer sub-type related to BRCA1-related risk-modifying variants.

In particular, they discovered that BRCA1 risk-modifying variants on chromosome 19 tend to coincide with estrogen receptor negative rather than estrogen receptor positive breast cancers.

For instance, they reported that two of the SNPs were associated with estrogen receptor negative cancers in 6,800 breast cancer cases and 6,613 controls recruited through the UK's Studies of Epidemiology and Risk Factors in Cancer Heredity study.

Similarly, when they looked at more than 2,300 breast cancer cases and nearly 4,000 controls recruited as part of an international consortium focusing on triple-negative breast cancer, the researchers explained, they found that five 19p13 SNPs coincided with triple negative breast cancer.

Those involved in the study speculated that the BRCA1 breast cancer risk-modifying variants might cause functional changes to nearby genes such as C19orf62, which codes for a protein called MERIT40 that interacts with the BRCA1 protein within a larger protein complex. Still, they emphasized, more research is needed to explore the functional consequences of the chromosome 19 SNPs and their role in modulating BRCA1-related breast cancer risk.

"[U]ntil the SNPs that increase risk of cancer have been definitively linked to MERIT40, it remains possible that the other genes in the region or genes influenced by long range chromatin remodeling or by transcriptional events account for the breast cancer association," they wrote.

Nevertheless, the findings so far point to the possibility of further stratifying individuals at risk of breast cancer, the researchers concluded, and suggest studies focused on certain breast cancer sub-types could help root out additional risk variants.

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