PROBABILITY OF CARRYING A MUTATION OF BREAST-OVARIAN CANCER GENE BRCA1 BASED ON FAMILY HISTORY

Background: Heritable mutations of the breast cancer gene BRCA1 are ra re, occurring in fewer than 1% of women in the general population, and therefore account for a small proportion of cases of breast and ovari an cancers, Nevertheless, the presence of such mutations is highly pre dictive of the development of these cancers. Purpose: We developed and applied a mathematic model for calculating the probability that a wom an with a family history of breast and/or ovarian cancer carries a mut ation of BRCA1. Methods and Results: As a basis for the model, we use Mendelian genetics and apply Bayes' theorem to information on the fami ly history of these diseases. Of importance are the exact relationship s of all family members, including both affected and unaffected member s, and ages at diagnosis of the affected members and current ages of t he unaffected members. We used available estimates of BRCA1 mutation f requencies in the general population and age-specific incidence rates of breast and ovarian cancers in carriers and noncarriers of mutations to estimate the probability that a particular member of the family ca rries a mutation. This probability is based on cancer statuses of all first- and second-degree relatives. We first describe the model by con sidering single individuals: a woman diagnosed with breast and/or ovar ian cancer and also a woman free of cancer. We next considered two art ificial and two actual family histories and addressed the sensitivity of our calculations to various assumptions. Particular relationships o f family members with and without cancer can have a substantial impact on the probability of carrying a susceptibility gene. Ages at diagnos is of affected family members and their types of cancer are also impor tant. A woman with two primary cancers can have a probability of carry ing a mutation in excess of 80%, even with no other information about family history. The number and relationships of unaffected members, al ong with their current ages or ages at death, are critical determinant s of one's carrier probability. An affected woman with several cancers in her family can have a probability of carrying a mutation that rang es from close to 100% to less than 5%. Conclusion: Our model gives inf ormative and specific probabilities that a particular woman carries a mutation. Implications: This model focuses on mutations in BRCA1 and a ssumes that all other breast cancer is sporadic. With the cloning of B RCA2, we now know that this assumption is incorrect. We have adjusted the model to include BRCA2, but the use of this version must await pub lication of penetrance data for BRCA2, including those for male breast cancer that are apparently associated with BRCA2 but not with BRCA1. The current model is, nevertheless, appropriate and useful. Of princip al importance is its potential and that of improved versions for aidin g women and their health care providers in assessing the need for gene tic testing.