Modifying effect of reproductive risk factors on the age at onset of breast cancer for GermanBRCA1 mutation carriers

Abstract

Female carriers of mutations in theBRCA1 gene on chromosome 17q have a very high risk of developing breast and/or ovarian cancer during their life-time. There is, however, little knowledge of to what extent non-genetic risk factors, such as age at menarche, age at first birth, and body mass index, alter the age at onset of disease. We identified individuals showing a high probability of linkage toBRCA1 and examined the effect of other known risk factors on disease risk. A total of 43 families with at least three breast or ovarian cancer cases, including two affected before 60 years of age, were studied for linkage to the susceptibility locusBRCA1. Blood samples from relevant family members were used to genotype for at least three chromosome 17q polymorphic markers. Information on reproductive history, hormone use and lifestyle factors was collected from female members using a self-administered questionnaire. Diagnoses of breast and ovarian cancer were verified through pathology reports and paraffin blocks were obtained when available. Multipoint LOD (logarithm of the odds) scores were calculated and individuals from 10 families with a posteriori probability for linkage greater than 0.90 were used for further analysis. Forty-sixBRCA1 carriers were identified by the disease haplotype; 30 were affected with breast cancer and 5 with ovarian cancer. Proportional-hazards analysis of age at onset of breast cancer yielded increased relative risks of 1.74 for early age at menarche (BRCA1 carriers. However, considering that our analyses were based on limited numbers, these results warrant further clarification.