Analysis of breast cancer gene variations will boost testing

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Researchers have analyzed nearly 4,000 mutations deliberately engineered into the BRCA1 gene, a process which will immediately benefit people undergoing genetic testing for breast or ovarian cancer risk.

The BRCA1 gene suppresses tumors, but scientists haven’t fully understood exactly how it does this, though certain mutations in the gene predispose women to breast and ovarian cancers.

If a healthy woman undergoes genetic testing and a cancer-predisposing mutation is found, surgery or more frequent screening can greatly reduce her risk of ever getting those types of cancer.

However, many women undergoing genetic screening for breast and ovarian cancer learn that their BRCA1 gene contains a variant of uncertain significance. This is a mutation that is not currently known to cause cancer, but theoretically could. BRCA1 is an exceptionally well-studied gene, but at present thousands of mutations in it fall into this category. Their implications for cancer risk are unknown.

“For example, I might sequence the BRCA1 gene in a woman and observe that she has a mutation, but I don’t know whether that mutation will actually lead to an increased risk of breast cancer or whether it will be perfectly harmless,” says Greg Findlay, an MD/PhD student in the physician-scientist training program at the University of Washington Medical School and lead author of the paper, which appears in Nature.

The challenges of BRCA1 testing

These variants of uncertain significance fundamentally limit the clinical utility of a patient’s genetic information. There is a concern, Findlay says, that women who harbor variants that indeed lead to cancer are not identified during genetic testing, and therefore are not presented with options that might allow them to avoid breast cancer or detect it in its more treatable stages.

Researchers have sequenced the BRCA1 gene in millions of women in the United States alone over the past decade. Geneticist and epidemiologist Mary-Claire King proposed the idea that mutations in a gene could account for some cases of breast cancer, as well as the mapping of the BRCA1 gene’s location on chromosome 17, in 1990 after reviewing breast cancer inheritance patterns in families.

“Frequently women are being tested for BRCA1 mutations because they have a family history of breast or ovarian cancer,” says Lea Starita, faculty in the genome sciences department. “To be told that they have a genetic variant in this cancer predisposing gene, but that the doctor doesn’t know what it means, does not reduce their stress or their anxiety.”

“The challenge with BRCA1 testing, and with genetic testing more generally, is even though the cost of genome sequencing has plummeted, we continue to have trouble interpreting what that information means,” says Jay Shendure, also faculty in the genome sciences department.

“The premise of precision medicine that we’ve been promising for 10 or 15 years now is that we’ll sequence the genomes of ordinary citizens, and that information will improve their health outcomes. We hope this new study brings us one step closer to delivering on that promise,” Shendure says.

Myriad gene versions

To help clinicians and patients obtain better information about genetic variants, Findlay developed a research approach called saturation genome editing, which relies on CRISPR, an enzyme tool that cuts strands of DNA to modify its sequence.

With the new tool, researchers made thousands of miniscule revisions in the BRCA1 gene, including changes that have not yet been seen in a human. Then they measured the effects of each mutation to see which ones caused problems in human cells growing in a dish.

“Being able to break it down at the level of single base pairs of DNA was pretty exciting,” the researchers say. “We found that you can study changes in the BRCA1 gene in the lab, and they reflect with surprising accuracy what happens in a person with that variant. Even though we’re working with cells in a dish, when we put changes into the genomes of those cells, and look at the places where the right answers should be, they almost always line up with what we observe in patients.”

Previously, researchers could only examine a few different mutations at a time. Now, the means to edit a gene into myriad versions is making it easier to understand how our DNA functions.

“We are basically categorizing all of the possible changes across critical regions of the BRCA1 gene as either behaving like disease-causing mutations or not,” Findlay says. The researchers needed about six months to test almost 4,000 mutations. They are extending this work to cover the entire BRCA1 gene over the next couple of years.

Gene testing blueprint

The researchers are quickly releasing newly available variant information through the Brotman Baty database to assist patients and clinicians trying to figure out what a test result might mean.

“Our hope is that this database will continue to grow and will become a central point for guiding the interpretation of actionable variants as they are first observed in women,” Starita says.

“The ability to study in a dish what will happen in a living, breathing human, at scale, opens up a lot of possibilities in medical genetics,” Shendure adds. The scientists also plan to apply the saturation genome editing methods to other cancer risk genes.

“The study serves as a blueprint,” Findlay says, “for how to test rare mutations in important genes that have big consequences for human health.”

The Brotman Baty Institute for Precision Medicine, a National Institutes of Health Pioneer Award, and a training award from the National Cancer Institute funded the work.

Source: University of Washington