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Team Begins Defining Cancer Risk Patterns for Distinct BRCA1, BRCA2 Mutations


NEW YORK (GenomeWeb) – In a study appearing online today in the Journal of the American Medical Association, researchers began to tease apart the differences in breast and ovarian cancer risk for women carrying various BRCA1 and/or BRCA2 gene mutations.

The international team, which included members of the "Consortium of Investigators of Modifiers of BRCA" (CIMBA) group, considered documented disease patterns for tens of thousands of women with BRCA1 or BRCA2 mutations.

When the researchers classified glitches in the genes based on their position, predicted severity, and so on — together with individuals' cancer diagnosis histories — they uncovered several so-called breast cancer cluster regions or ovarian cancer cluster regions in BRCA1 and BRCA2.

"The results of this study are a first step in understanding how to personalize risk assessment around a woman's specific mutation, which can help guide carriers and providers in the cancer prevention decision-making process," the study's first author Timothy Rebbeck, an epidemiology researcher and associate director of population science at the University of Pennsylvania's Abramson Cancer Center, said in a statement.

Past studies have hinted that women with mutations falling after the 11th exon in BRCA1 have somewhat lower risks of ovarian cancer than those with coding mutations in earlier coding portions of the gene, the team noted. On the other hand, mutations in exon 11 of BRCA1 or in BRCA2's 11th exon have been linked more closely to ovarian cancer risk than to risk of breast cancer.

But despite these and other hints, more research is needed to untangle the breast and ovarian cancer burdens that coincide with various BRCA1/2 mutations.

With that in mind, members of the CIMBA group and their collaborators set out to scour de-identified data from centers around the world for 19,581 women who carried mutations in BRCA1 and 11,900 BRCA2 mutation carriers.

All of the BRCA1/2 mutations had been deemed pathogenic based on their location and/or predicted effects, the team noted, and individuals with both BRCA1 and BRCA2 mutations were not considered in the study.

Just under half of the BRCA1 mutation carriers — some 46 percent — were diagnosed with breast cancer alone. Another 12 percent developed ovarian cancer, while 5 percent were diagnosed with both breast and ovarian cancer. Just over one-third of the individuals with BRCA1 mutations remained breast and ovarian cancer-free.

Some 52 percent of individuals with BRCA2 mutations received a breast cancer diagnosis, the researchers reported, and 6 percent had ovarian cancer. Two percent of the BRCA2 mutation carriers developed both breast and ovarian cancer, while 40 percent were not diagnosed with either disease.

In both genes, the team saw stretches of sequence where damaging mutations were more closely tied to cancer risk. For example, the analysis highlighted three breast cancer clusters and one ovarian cancer cluster in BRCA1.

Whereas BRCA1 mutation carriers in general appeared to have a 59 percent risk of developing breast cancer by the age of 70, the researchers saw an elevated risk of the disease in individuals with certain mutation types, including missense mutations or a founder mutation that's been linked to Ashkenazi Jewish populations.

In contrast, the founder mutation appeared to carry a slightly lower ovarian cancer risk compared with other mutation types in BRCA1.

Rebbeck and the co-authors cautioned that "further systematic studies will be required to determine the absolute cancer risks associated with different mutations." Still, they argued that "knowledge of mutation-specific risks could provide important information for clinical risk assessment among BRCA1/2 mutation carriers."