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The BROCA Test

A New Way to Detect Mutations that Cause Ovarian Cancer

by Clayton Boldt

We have long known that women with a family history of breast and/or ovarian cancer are at higher risk for developing cancer in the ovaries, fallopian tubes, and the peritoneum. This knowledge dates back to the 19th century, when French physician Pierre- Paul Broca became one of the first to describe inherited breast and ovarian cancers. Now, he is honored as the namesake of a new test for identifying cancercausing mutations.

Dr. Tom Walsh and colleagues at the University of Washington designed the BROCA test to detect mutations in 12 tumor-suppressor genes that cause inherited breast and ovarian cancer. When tumor-suppressor genes work correctly, they help our bodies repair damage to DNA that occurs over time due to aging or other factors. Several of these genes are part of an enzyme "pathway" in our cells called the Fanconi Anemia pathway, which cooperates with BRCA1/2 genes to regulate DNA damage repair.

In a recent study, Dr. Walsh used the test to determine the percentage of ovarian cancers caused by hereditary mutations in those genes. The research involved 360 women who were diagnosed with ovarian, primary peritoneal, or fallopian tube carcinomas. Researchers reported that 24% of the women carried lossof- function mutations in at least one of the genes analyzed; 18% of these women had mutations in BRCA1 or BRCA2, a prevalence that is slightly higher than reported in previous research. However, of the remaining women, 6% had mutations in at least one of the other genes, including six new genes that had never before been implicated in hereditary ovarian cancers.

Interestingly, despite the high proportion of women in this study with inherited mutations, participants were not selected for age or family history. In fact, over 30% of patients with mutations had no personal or family history of breast or ovarian cancer. More than one-third of the women were over 60 years old at diagnosis, and there was no significant association with age and likelihood of carrying a mutation. Based on this research, selecting patients for genetic testing by age and/or family history would exclude a tremendous number of women carrying potentially cancer-causing mutations.

BROCA can simultaneously detect any type of mutation in multiple genes from a single sample, for a lower cost than Myriad Genetics — two tests that assess BRCA1/2 mutations. Unfortunately, the patent held by Myriad Genetics prohibits other labs from reporting BRCA gene mutation results, so BRCA testing must be conducted separately from the BROCA test. (A legal challenge to Myriad's patent, which expires in 2015, is expected to reach the Supreme Court this year.) However, the University of Washington is offering BROCA as a clinical test for 40 genes in patients who test negative for BRCA1/2 mutations. BROCA testing includes all known colon, pancreatic, and melanoma cancer genes, in addition to all known breast and ovarian cancer genes, making it even more powerful.

As technology improves, the need to create and implement improved genetic testing approaches such as BROCA becomes apparent. Adopting this and other more comprehensive tests will dramatically improve the ability to identify and help those with inherited cancer risk.

BROCA Reference

Walsh T, Casadei S, Lee MK, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proceedings of the National Academy of Sciences vol. 108, no. 44 (2011): 18032-37.

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