Gene Panel Spots Mutations Other Breast Cancer Test Misses

Neil Osterweil

October 25, 2013

BOSTON — The US Supreme Court ruling that genes can't be patented is good news for members of families with a history of breast or ovarian cancer.

That's the opinion of investigators who, freed by the landmark decision, developed a comprehensive genetic panel. They say it can identify mutations in approximately 25% of patients who had normal results on a commercial assay for BRCA1 and BRCA2 mutations (BRACAnalysis, Myriad Genetics).

"The recent US Supreme Court decision that invalidates gene patenting has really opened the door to apply modern genomic technologies to the screening of breast cancer using cancer panels and next-generation sequencing. We're now able to test, in a single assay, all known breast cancer genes, and at the same time evaluate all mutation classes — small mutations as well as complex genomic deletions and duplications," said Tomas Walsh, PhD, associate research professor of medical genetics at the University of Washington in Seattle.

Dr. Walsh presented the research here at the American Society of Human Genetics 63rd Annual Meeting.

The assay developed by Dr. Walsh and his team, known as BROCA, can detect all single base substitutions, insertions, and deletions, and copy number variants in all 26 genes known to be implicated in breast cancer.

They tested the assay in 2285 members of 740 families in which 3 or more relatives had invasive breast or ovarian cancer, and at least 1 woman with breast cancer received normal results on the commercial assay.

The recent US Supreme Court decision that invalidates gene patenting has really opened the door to apply modern genomic technologies to the screening of breast cancer.

In 191 of the families, mutations in 18 genes "resolved" or explained at least some of the risk, and in 66 of these families (35%) there were mutations in BRCA1 and BRCA2.

The results indicate that "referral guidelines should be extended from BRCA1/2 only to multigene panel testing for breast cancer predisposition," Dr. Walsh said.

The American Cancer Society recently changed its recommendations on screening for high-risk patients based on the ability to identify BRCA1/2 and other genes susceptible to breast cancer.

"The current recommendation is that you consider annual MRI for high-risk individuals, however you define them," said Olufunmilayo Olopade, MD, Walter L. Palmer Distinguished Service professor in medicine and human genetics at the University of Chicago, in a briefing. Dr. Olopade was lead author of a related study, in which BROCA identified 9 genes for inherited predisposition to breast cancer in black women.

The availability of a comprehensive assay that uses contemporary sequencing techniques will improve the clinical care of women at risk for breast cancer, Dr. Olopade noted.

"Now we can do better risk stratification, and there are better options for these women that go beyond having prophylactic mastectomy. I think that's really where we can put this in the context of personalized risk assessment and screening," she said.

"There's nothing magic about this," said Lawrence Brody, PhD, chief and senior investigator at the Genome Technology Branch, National Human Genome Research Institute, in Bethesda, Maryland.

"It's just known genes that are put on a panel. The idea of looking at more than just BRCA1 and BRCA2 is an obvious thing to do, but the technology limited it until next-gen sequencing came online," he told Medscape Medical News.

He emphasized that the inclusion of the additional genes in the panel does not mean that they confer a risk equivalent to that of BRCA1 and BRCA2.

Some of the mutations, such as those in CHEK2, are known to be present in approximately 1% of women without breast cancer and 2% of women with breast cancer. In contrast, BRCA1 is present in roughly 5% of women with breast cancer, but in only about 0.001% of women in the general population. The differential effect, therefore, is far larger than with the other mutations screened for in the panel, Dr. Brody said.

"The conundrum you have to deal with is what to do with this information," he said.

Nonetheless, the information provided by the assay can help direct research toward better methods for prevention, screening, and treatment, said James Dermody, PhD, director of the Molecular Diagnostic Laboratory at Rutgers New Jersey Medical School in Newark, who was not involved in the study.

"It looks like there are as many mutations in these other genes as were initially found with BRCA1 and BRCA2, which is a really relevant piece of information, especially in the early-onset cases," he told Medscape Medical News.

This study was supported by the Breast Cancer Research Foundation, the National Cancer Institute, the Congressionally Directed Medical Research Program of the US Department of Defense, and the Susan G. Komen Foundation.

American Society of Human Genetics (ASHG) 63rd Annual Meeting. Abstract 90. Presented October 24, 2013.


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