The objective of this study is to investigate gene-environment interactions influencing susceptibility in the etiology of breast cancer. We propose to establish a repository of epidemiologic risk factor information and biologic specimens from 700 women with asynchronous bilateral breast cancer and 1400 women with unilateral breast cancer who will be ascertained through 5 population-based tumor registries in the US and Denmark. All subjects will be interviewed using a structured questionnaire and blood samples will be collected for genetic analyses. Our initial plan for using this repository is to examine the interaction of radiation exposure, the ATM gene, and breast cancer. Ionizing radiation is known to be a breast carcinogen and recent studies suggest that the ATM gene may increase susceptibility to radiation-induced breast cancer. Our hypothesis is that women who are ATM gene carriers and who have received radiation therapy as part of breast conservation treatment, are at especially high risk of developing second primary contralateral breast cancer. We will also provide descriptive statistics on the prevalence of ATM in this large population-based sample of women. ATM heterozygosity will be assessed through an efficient staged approach appropriate for analysis of this complex gene. For subjects who received RT, radiation scatter dose to the contralateral breast will be reconstructed.

The unique repository that we establish will be critical for future interdisciplinary investigations into the mechanisms and nature of gene-gene and gene-environment interaction influencing susceptibility to breast cancer. The study of second primaries presents a particularly promising context in which to disentangle the complex interactions among hormonal, genetic, and environmental factors influencing breast carcinogenesis as any important etiologic factors (e.g. genetic abnormalities) will be more prevalent among women who already have breast cancer than in the general population. Further, the rising incidence of breast cancer coupled with improved survival, has placed an increased number of women at risk for second primary breast cancer making it an issue of public health importance.

Deficiencies in cellular responses to DNA damage can predispose to cancer. However, the gene- environment interactions that may be involved in the etiology of these cancers are poorly understood. One important environmental cause of DNA damage is exposure to ionizing radiation leading to the formation of DNA double-strand breaks (DSB). Recent evidence demonstrates that three genes in which mutations predispose to breast cancer, BRCA1/2 and ATM have complex interactions with each other and are essential for the normal cellular response to DSBs. Therefore, interaction between alleles at these loci may have important effects on breast cancer risk, in general, and radiation-induced breast cancer, in particular. To delineate the roles of radiation exposure and genetic predisposition in the etiology of breast cancer, we propose to determine the prevalence of BRCA1/2 mutations in the 2100 WECARE study participants with unilateral or bilateral breast cancer for whom blood samples have already been obtained and ATM mutation status already determined. Our study hypothesis is that the incidence of contralateral breast cancer will be increased among women who are carriers of mutant BRCA1 or BRCA2 alleles and who received RT as part of treatment for first primary breast cancer. The 700 cases are women with bilateral breast cancer individually countermatched to two controls, women with unilateral breast cancer.