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Study: Current Testing of BRCA Genes Misses Some Variants; Family History Still Best Guide

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Ethnic minority women in the United States are less likely to carry one of the BRCA1 or BRCA2 gene variants recognized as risk factors for breast cancer, and more likely to carry variants of unknown significance that might be useful as predictors of disease, but due to intellectual property constraints, new diagnostics and the recognition of new clinically relevant BRCA variants will be hindered, though that may not be the case for sequences outside those genes. In the meantime, research published this week in the Journal of the American Medical Association demonstrates that it makes just as much sense to estimate the risk of breast cancer in ethnic minorities using the traditional familial genetics method used with Caucasians and Ashkenazi Jews.

"You could look at it as a cup that is either half empty or half full," said Funmi Olopade, co-author on the paper and director of the Center for Clinical Cancer Genetics at the University of Chicago Medical Center. "In the African-American women that we tested, well over 30 percent of them had a definitive answer to the question of whether they had a [BRCA-1 or -2] mutation or not, and in the other women, about 45 percent of them had an answer," she said. "So even in the women who are non-Ashkenazi Jewish, the majority still didn't have a definitive answer," but genetic counseling and testing are commonly in clinical use to recommend risk-reduction strategies, Olopade added.


"One of our greatest limitations is the testing technology, and we know that there are probably better tests that have yet to be discovered to look at BRCA1 and -2 more thoroughly."

Not enough ethnic minority women have been tested yet to determine whether other sets of BRCA-related genetic variants are indeed more important predictors of breast cancer, said Olopade. However, it is known that the spectrum of mutations in BRCA1 and BRCA2 in African-Americans, for example, is "vastly different" from that of Caucasians, she said. "We have no data on Hispanic-Americans or Asians — as much as this is a very diverse country, we better get our act together and inform physicians on how to get more ethnic minorities to participate in genetic research."

The gene variations recognized to contribute to a significant risk of breast cancer were identified in Ashkenazi Jewish women because the genetics of this group are well characterized, said Olopade. Just how the spectrum of deleterious mutations differs in other ethnic groups is not known, she said. "The statistical model that we use, when we apply it to African-Americans and women of European ancestry, does it work about the same? It does," she said.

The BRCA1 and -2 mutations recognized as dangerous are generally nonsense mutations — those in which the gene's protein product is truncated — and about 30 missense mutations, in which an amino acid has been substituted, according to Fergus Couch, an associate professor of laboratory medicine at the Mayo Clinic in Rochester, Minn. Couch estimated that as many as 1,500 deleterious mutations within the BRCA genes remain unrecognized.

The only BRCA1 and -2 diagnostic on the market is a sequencing test made by Myriad Genetics, which has been used for about 10 years in more than 100,000 women, said Bill Hockett, a Myriad spokesperson. The company markets the test the same way for US ethnic minorities and Caucasians — women with a familial history of breast cancer are its target.

In the United States, Myriad's patents prevent competing companies from creating diagnostics of their own for BRCA1 and -2, unless any genetic variations tested lie beyond the region bounded by Myriad's patents.

"Frankly, the [Myriad BRCA test] is one of those that has been somewhat difficult," said Mike Watson, director of the American College of Medical Genetics, a professional association that often recommends panels of clinically relevant gene variants for testing in different diseases. "We tend not to get into tests that are proprietary, because we can't access the kind of data that we'd need to make independent decisions about [BRCA1 and -2]," he said.

"One of our greatest limitations is the testing technology, and we know that there are probably better tests that have yet to be discovered to look at BRCA1 and -2 more thoroughly," said Shelly Cummings, a co-author of the JAMA article and a researcher at the Center for Clinical Cancer Genetics. The sequencing test is limited because it can miss some mutations, such as regulatory regions and even some types of deletions and re-arrangements, she said. "When the test was first developed, huge deletions would not show up," but Myriad went back to correct the problem, she added.

Couch, the Mayo Clinic researcher, estimated that as many as 10 percent of BRCA1 and -2 tests report an "unclassified" variant — a mutation with unknown significance. "It's certainly true that there are more unclassified variants in African-Americans — perhaps twice as many," he said.

Myriad is "always trying to understand what these variants are" through its own work and in collaboration with other researchers, said Couch. By combining epidemiological and laboratory research, the company and academics like Couch hope to classify variants of unknown significance, he said. "In the end, it will prove to be part of the test that Myriad currently offers."

The field is basically open for diagnostics in other countries, however. In Canada and Europe, Myriad's BRCA patents have been ruled invalid, except in some situations involving Ashkenazi Jewish patients, said Couch. "To give Myriad credit, they are trying to resolve with all possible haste" which mutations are most relevant, he said. For example, at the American Society of Human Genetics meeting in Salt Lake City, next week, Myriad plans to present data showing that 56 variants of unknown significance are neutral mutations, he added.

— Chris Womack ([email protected])

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