Public Release: 

Risk from breast cancer susceptibility gene may be exaggerated in most studies

Journal of the National Cancer Institute

An analysis of past studies on mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 suggests that estimates of penetrance (or the likelihood that mutation carriers will develop breast cancer during their lifetime) have been exaggerated. This can happen because a woman's risk of developing breast cancer is likely to be associated not only with the specific genetic mutation but also with many other risk factors, concludes a study in the August 21 issue of the Journal of the National Cancer Institute.

Accurately estimating penetrance is important for genetic counseling because the estimates may influence decisions about cancer prevention, such as whether to undergo a prophylactic mastectomy. Early studies examined families that had multiple cases of breast cancer and resulted very in very high penetrance estimates--in the range of 71% to 85% by 70 years of age.

To avoid this problem, more recent studies have used women with breast cancer who do not necessarily have a strong family history of the disease. These studies have resulted in considerably lower estimates. But this strategy, too, is biased and can still lead to inflated penetrance estimates, according to study author Colin B. Begg, Ph.D., of the Memorial Sloan-Kettering Cancer Center, New York.

He argues that all risk factors for breast cancer are over-represented in incident cases of breast cancer. This means that a sample of women who have been diagnosed with breast cancer who are identified as mutation carriers are more likely to also have other breast cancer risk factors than similar mutation carriers who are disease-free. The current strategy for estimating risk is unbiased only if all carriers share an identical risk of developing the disease, he says.

Begg concludes that, "substantial heterogeneity exists in the risk for cancer among individuals in the population." He points out that the presence of a BRCA mutation in a woman does not completely define her risk for breast cancer because in addition, numerous unknown risk modifiers are likely to exist. He says these modifiers should be reflected in the tools used by genetic counselors to predict risk.

In an accompanying editorial, Wylie Burke, M.D., Ph.D., and Melissa A. Austin, Ph.D., of the University of Washington in Seattle, say the new study underscores the pitfalls of failing to address the complexity of disease risk and its implications for disease prevention. They point out that nongenetic risk factors have been shown to influence the outcome of genetic risk in other settings. For example, they say, smoking, diet, and exercise can modify the effect of genetic risk for heart disease.

"Without a healthy respect for the many factors that may influence penetrance, we will continue to overestimate the risk conferred by BRCA1 and BRCA2 mutations alone and, thus, miss opportunities to develop truly effective prevention strategies for women who are genetically susceptible to breast cancer that are based on a broad understanding of causative factors," they say.


Contact: Christine Hickey, Memorial Sloan-Kettering Cancer Center, (212) 639-3573, fax: (212) 639-3576,

Editorial: Walter Neary, University of Washington, Seattle, (206) 685-3841, fax: (206) 685-3333,

Begg C. On the use of familial aggregation in population-based case probands for calculating penetrance. J Natl Cancer Inst 2002;94:1221-6.

Editorial: Burke W, Austin M. Genetic risk in context: calculating the penetrance of BRCA1 and BRCA2 mutations. J Natl Cancer Inst 2002;94:1185-7.

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