Penetrance of Mutations
The proportion of individuals carrying a mutation who will manifest the disease is referred to as penetrance. For adult-onset diseases, penetrance is usually dependent upon the individual carrier's age and sex. For example, the penetrance for breast cancer in female BRCA1/BRCA2 mutation carriers is often quoted by age 50 years (generally premenopausal) and by age 70 years. Of the numerous methods for estimating penetrance, none are without potential biases, and determining an individual mutation carrier's risk of cancer involves some level of imprecision.
Estimates of penetrance by age 70 years for BRCA1 and BRCA2 mutations show a large range, from 40% to 87% for breast cancer and 10% to 68% for ovarian cancer. Refer to Table 3 and Table 4 for cumulative incidence data from several studies of cancer penetrance among BRCA1 and BRCA2 mutation carriers.[102,103,104] Initial penetrance estimates for BRCA1 and BRCA2 mutations were derived from multiple-case families from the Breast Cancer Linkage Consortium (BCLC), families studied to localize and clone the genes.[15,105,106] For breast cancer, the estimates ranged from 50% to 73% by age 50 years and 65% to 87% by age 70 years for BRCA1, and 59% and 82% by ages 50 years and 70 years, respectively, for BRCA2. For ovarian cancer, the estimates were as high as 29% by age 50 years and 63% by age 70 years.[105,106] For many patients currently seeking genetic testing for BRCA1 and BRCA2, the family history will not be as strong as this study by the BCLC (e.g., more than four affected relatives in the same biologic lineage) and therefore, these estimates may not apply.
In addition to the estimates from multiple-case families and patients from high-risk genetics clinics,[12,15,105,106,107,108,109,110] at least 13 studies have estimated penetrance by studying the families of mutation carriers who were not specifically recruited and studied because of a positive family history.[46,52,55,56,61,86,103,108,111,112,113,114,115] Often these studies have concentrated on founder populations in which testing of larger, more population-based subjects are possible owing to a reduced number of mutations that require testing,[55,61,86,111,113,115,116] compared with complete sequencing of the two genes required in most populations. The first study of a community-based series was carried out in the Washington, DC area. Blood samples and family medical histories were collected from more than 5,000 Ashkenazi Jewish individuals. Study participants were tested for three founder mutations: 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2. The prevalence of breast cancer in the relatives of carriers was compared with that reported by mutation-negative individuals. The risk of breast cancer in carriers of these mutations was estimated to be 56% (95% confidence interval [CI], 40%-73%) by age 70 years. Ovarian cancer risk was estimated to be 16% (95% CI, 6%-28%). These values were lower than most prior risk estimates.