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Angelina Jolie opted to have surgery after learning she had inherited a mutation in the BRCA1 gene.

At-risk. Angelina Jolie opted to have surgery after learning she had inherited a mutation in the BRCA1 gene.

Greg Skidmore/Wikimedia

Researchers Spar Over Tests for Breast Cancer Risks

BOSTON—A heated discussion broke out here today at the annual meeting of the American Society of Human Genetics over a hot-button topic: When will we know enough about rare cancer risk genes to begin routinely testing for them in patients with a family history of cancer?

On one side of the debate was a team led by breast cancer geneticist Mary-Claire King, who discovered the first inherited breast cancer risk gene, BRCA1. King’s group now wants to routinely test certain women for other cancer-linked genes. Other researchers, however, argued that it is premature to test for these other genes, which are less well understood.

Doctors often offer women with breast cancer in their family testing for mutations in BRCA1 and a related gene, BRCA2. If the tests are positive, some women may take preventive measures. Earlier this year, for example, actress Angelina Jolie drew widespread attention for her decision to have a double mastectomy because she inherited a version of BRCA1 that carries an 87% risk of developing breast cancer.

Many women with breast cancer in their family don’t test positive for BRCA mutations, however. At the meeting, Tomas Walsh of the University of Washington, Seattle, reported on a test he and King developed, called BROCA, that sequences not only the BRCA genes, but also about 38 other cancer risk genes. They ran the BROCA test on nearly 2300 women from 743 families with breast cancer. In 77 families, they did not find BRCA mutations, but did find changes in other genes they say are definitely linked to breast cancer, such as TP53 and CHEK2. Another 41 families carried mutations in a larger set of genes whose role in cancer is “emerging,” Walsh said.

King and Walsh aren’t just using their BROCA test in research, however—their university is also offering it as a clinical test to patients. And physicians elsewhere can order the commercial test.

That did not sit well with other researchers in today’s session. “It is irresponsible and unacceptable” to clinically test for genes other than BRCA for which risks aren’t well established, said Nazneen Rahman of the Institute of Cancer Research in Sutton, U.K. Doing so is “damaging,” she tells ScienceInsider, because it could lead women to take drastic steps such as having their breasts removed. King’s team has “mixed up research and clinical” testing, she said.

King’s group defended their test in a discussion with reporters. Physicians receive results only for 12 genes that the evidence suggests can double or quadruple the risk of cancer; that translates to a 25% to 50% chance of a woman developing breast cancer, Walsh said. When the team detects these genes, they do not recommend surgery, but instead regular screening with imaging.

King points out that testing for BRCA1 was controversial before the community came to a consensus in 1997. “I have a sense of déjà vu,” she tells ScienceInsider. She said her critics mistakenly think the clinical BROCA test returns results for all 40 genes, not just the 12. “We’re comfortable about the ones for which we already have data,” based on their own studies and the literature, she said. “We have been extremely conservative in not reporting back variants” of uncertain significance, she said.  

Surgeon Greta Bernier from King’s group added that while testing only for BRCA genes is recommended by the National Comprehensive Cancer Network, which issues guidelines for cancer treatment, her team is hopeful that the network will soon add more genes on their list. She also points out that physicians can already order tests for the genes on her team’s list from gene-testing companies.

Melissa Southey of the University of Melbourne in Australia believes that while it’s important to test for all cancer risk genes in research, the evidence for clinical testing is strong enough only for a few genes, and even then only for a few specific variants. The problem, she says, is that many of the other variants are so rare that it may never be possible to study enough people to pin down the risks. Instead, researchers will have to rely on other evidence that the mutations are harmful, such as lab studies of the proteins encoded by the genes.

The same difficulty will confront geneticists as they discover other rare disease risk genetic variants, Southey adds. “This is the edge, where we are,” she says. “We have a lot of information, but not enough to offer advice.”