ing the penetrance of BRCA genes. Some studies find that a woman’s reproductive history can modify the penetrance of BRCA1 or BRCA2 (reviewed by Burke and Austin, 2002).10 Other studies find that cancer risk is relatively greater in younger women who test positive for BRCA mutations than in older women.10,45 Birth cohort and physical exercise also have been shown to partially mitigate the influence of BRCA1.45 Ashkenazi Jewish women born with one of the three mutations associated with Ashkenazi ancestry who were born before 1940 have an average lower likelihood of developing breast cancer than similar women born after 1940. In the same study, women with those mutations who had been physically active as teenagers and were not obese as young adults showed an approximate risk reduction of 10 years—that is, a 60-year-old woman who was not obese at age 21 and with a history of physical activity had approximately the same average risk as a 50-year old woman with a history of obesity and no physical activity. Such a change in penetrance over time is likely due to the influence of a changing environment.

As Wylie Burke and Melissa Austin summarize in an editorial in the Journal of the National Cancer Institute:

The most important implication of penetrance studies should perhaps be to temper our expectations for predictive genetic tests. Without a healthy respect for the many factors that may influence penetrance, we will continue to overestimate the risk conferred by BRCA 1 and BRCA 2 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.10

The wide range of penetrance estimates complicates decisions for preventive interventions like prophylactic mastectomy or tamoxifen chemoprevention, although even the lowest penetrance estimates might be high enough to suggest that women who test positive for BRCA mutations should be screened more aggressively. However, one study found that annual mammograms and biannual physical exams were less sensitive, and detected tumors at later stages in women with BRCA mutations than in women at greater than average risk for breast cancer who lack the mutations.9 Furthermore, studies have found that BRCA2-deficient cells are hypersensitive to the effects of radiation,54 so there is concern (but so far no evidence) that women, especially those with BRCA2 mutations, might be susceptible to radiation-induced genetic defects and cancer.

Another problem is that researchers have detected more than 2,000 mutations of BRCA1 or BRCA2,54 but the clinical significance of these is not yet known; some may not influence breast cancer risk. Consequently, more than 1 in 10 BRCA tests yields inconclusive results because the clinical significance of the specific mutations detected by the tests is unknown.2



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