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Breast cancer susceptibility genes: Overstating the risk?


The risk for developing breast cancer and ovarian cancer is higher for women with mutations in the BRCA1 or BRCA2 genes, but how much higher has now become a matter of debate. Many predictions of the risk for cancer due to these mutations have been greatly overestimated, according to a new report by Colin Begg of Memorial Sloan-Kettering Cancer Center in New York.

Early studies, conducted in the mid-1990s, suggested that a woman with a mutation in the BRCA1 or BRCA2 gene could face a 70 to 85 percent chance of developing breast cancer by age 70. The problem with these estimates, according to Begg, lies in how the studies were conducted. They included subjects who presumably had more risk factors—both genetic and non-genetic—than women in the general population.

Begg argues that without being able to distinguish the contributions of genetic and other risk factors it is not possible to estimate accurately the effect of carrying BRCA1 or BRCA2 disease genes. The concern among doctors and researchers is that women with the mutations may use inflated estimates to make life-altering decisions, such as electing to have their breasts removed surgically in a procedure called prophylactic mastectomy.

The notion that a BRCA mutation completely defines a woman's risk for breast cancer is "probably far from the truth and, in fact, numerous unknown genetic risk modifiers are likely to exist," Begg writes in the Journal of the National Cancer Institute. Until researchers fully understand how these unknown factors modulate the effects of known BRCA mutations, estimating breast cancer risk will remain a very tricky business.

Some genetic counselors point out, however, that they are already providing women with a wide range of risk estimates. Katherine Schneider, a genetic counselor at the Dana-Farber Cancer Institute in Boston, Massachusetts, says that differences in risk estimates do not greatly affect how she counsels her patients. Most of the people she sees are there because of a family history of breast or ovarian cancer, not because they have been identified as a carrier of a BRCA mutation through genetic testing.

"For a long time we have been giving patients a wide range of risk estimates," says Schneider. "What we don't know is what other genetic modifiers are present that can affect the outcome of the disease."

Until more is known about these modifiers, Schneider recommends a cautious approach to genetic counseling. Whether a patient faces a 50 percent risk of developing breast cancer, or a 75 percent risk, the decisions are often similar, she says.

"A 50 percent risk is still very high," Schneider says. "Most patients will opt for an ovarectomy, which also decreases the risk of breast cancer, and for more diligent monitoring. Less than 10 percent of the patients we see will opt for prophylactic mastectomy."

The public health impact of this lies in the rush to do genetic screening, according to Teri Beaty of the Johns Hopkins School of Public Health in Baltimore. "We have the ability to identify many of the hundreds of different mutations in genes like BRCA1 and 2," she says. "But we can't offer very accurate estimates of risk to people who are identified as carriers but not yet affected by breast cancer."

This raises questions about who should be screened. "We can't offer proven preventive measures, and we can't even offer assurances of no risk to non-carriers," Beaty says.

To more accurately estimate risk, says Begg, researchers would need to screen a random sample of people from the general population for BRCA mutations, and then look for the number of cases of breast cancer among relatives who also have these mutations. Such studies, however, are difficult to conduct because few people in the general population harbor BRCA mutations.

Researchers have tried different strategies to overcome bias in assessing breast cancer risk. Jeff Struewing and colleagues at the National Cancer Institute in Bethesda, Maryland, recently screened 5,000 Jewish women in the Washington D.C. area for common BRCA mutations. After identifying relatives of the carriers who had breast cancer, the researchers estimated the risk of developing cancer for persons with mutations at 56 percent.

Other studies looking at BRCA mutations in populations other than breast cancer patients have produced estimates ranging from 28 to 74 percent.

Even the Washington study is not without bias, notes Begg, because privacy issues make it difficult to screen a completely random sample of individuals. "And people who present themselves to a clinic for testing may already have relatives with breast cancer."

Most researchers agree that it is important to continue to study all the other risk factors that may lead to breast and ovarian cancer. But until those factors are well understood, it may be premature to give an accurate assessment of cancer risk based on a single genetic mutation.

"Clear answers are rare in genetic epidemiology," says Beaty.

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Begg, C.B. On the use of familial aggregation in population-based case probands for calculating penetrance. J Natl Cancer Inst 94, 1221-1226 (August 21, 2002).
Burke, W. & M.A. Austin. Genetic risk in context: Calculating the penetrance of BRCA1 and BRCA2 mutations. J Natl Cancer Inst 94, 1185-1187 (August 21, 2002).

Struewing, J.P. et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336, 1401-1408 (May 15, 1997).

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