. Late-onset breast cancer is probably caused by the interaction of multiple genes, endogenous environments, and exogenous exposures. One consequence of this complex, multifactorial aetiology of breast cancer is that aetiologic heterogeneity may exist. Aetiologic heterogeneity implies that two or more groups of breast cancer cases in the general population are caused by different sets of aetiological events. The ability to define aetiologically-distinct (i.e., homogeneous) subgroups in the population may facilitate: 1) epidemiological studies to identify causative agents in breast cancer aetiology; 2) identification of optimal breast cancer diagnosis or treatment regimens; and 3) the targeted application of cancer detection and prevention strategies. A case-series study is proposed, that will focus on aetiologic heterogeneity in late onset breast cancer. This study will address three specific hypotheses. First, candidate susceptibility genotypes at the cytochromes P450 and glutathione-S-transferase loci will be evaluated for their capacity to define aetiologically heterogeneous case groups with respect to age at breast cancer diagnosis. Second, candidate genotypes will be evaluated for their capacity to define aetiologically heterogeneous case groups with respect to somatic genetic damage. Third, interactions of candidate susceptibility genotypes and somatic genetic mutation will be evaluated for their capacity to define aetiologically heterogeneous case groups. In order to address these hypotheses, a study will be conducted, using an existing subject accrual system to identify a sample of 600 incident, invasive breast cancer cases at the Hospital of the University of Pennsylvania (HUP). Risk factor information will be obtained from a questionnaire interview, a biosample containing DNA will be collected using a non-invasive cheek swab method, and pathology information will be collected using a standardized medical record abstraction approach. In addition, breast tumor and normal tissue will be obtained from half of these subjects for loss of constitutional heterozygosity analysis. The results of these analyses will be used to attempt to elucidate the complex, multifactorial aetiology of late onset breast cancer.
