INTERACTION OF NONGENETIC RISK FACTORS WITH BRCA1

DESCRIPTION: (Applicant's Description): BRCA1 and BRCA2 are clearly important determinants of breast cancer risk, but even within a family segregating a mutation, there is wide variability in the age-at-onset distribution. We hypothesize that differences in modifiable lifestyle factors influence this variability. Identification of factors associated with later age at onset may help inform approaches to risk reduction in individuals with a strong inherited predisposition to breast and/or ovarian cancer. A genetic study of breast cancer was conducted at the University of Minnesota using a consecutive series of patients between 1944 and 1952. We have successfully recontacted these families and extended the pedigrees to four- to five-generations. Detailed risk factor information has now been collected through telephone interviews, mailed questionnaires to assess anthropometrics and diet, mammography, and review of medical records and death certificates. These 426 breast cancer families include 260 with at least 2 affected individuals with breast or ovarian cancer, 132 of which contain 3 or more affected individuals. The 260 families will be screened for mutations in BRCA1 and BRCA2 using conformation sensitive gel electrophoresis (CSGE) and direct sequencing. In those families found to be segregating mutations, we will collect additional blood samples from other affected and unaffected members for mutation detection. Survival analysis using the Cox proportional hazards and accelerated failure time models will be carried out. Ample statistical power is available to detect gene x environment interactions as low as 1.75-fold. Given the wealth of risk factor data already collected on these families, we are in a unique position to identify how these factors modify expression and penetrance of the two major susceptibility genes for breast cancer in a well-characterized cohort of families. The results may help inform approaches to the primary prevention of cancer in these high-risk women.