P53 in BBD and Breast Cancer Risk: A Multicenter Cohort

DESCRIPTION (provided by applicant): The p53 gene plays a pivotal role in carcinogenesis. p53 gene changes are amongst the most commonly observed genetic alterations in many cancers, including breast cancer. For breast cancer, there is evidence to suggest that p53 gene changes occur relatively early in the carcinogenic process; hence, such changes might be associated with increased breast cancer risk. Therefore, in the nested case-control study proposed here, we intend to estimate the risk of breast cancer in association with p53 mutations and/or p53 protein accumulation in benign breast tissue obtained from 1,005 cases and 1,615 controls prior to the occurrence of breast cancer (for the cases) and at a comparable time (for the controls). Our work will be undertaken in a large, multi-center cohort of 25,843 women who were biopsied for benign breast disease and who have been followed-up to determine the subsequent occurrence of breast cancer. The cohort will be created by combining similar cohorts in Toronto, Canada (4,888 women), Portland (9,315 women), Detroit (5,146 women), and London, England (6,494 women). p53 protein accumulation will be detected immunohistochemically and p53 mutations will be detected using the p53 GeneChip, with manual direct sequencing for exon 4. Breast cancer risk in association with p53 changes will be estimated using conditional logistic regression. For a sample of cases, p53 changes in the benign tissue will be compared with those in the corresponding cancer tissue. Collections of archival paraffin blocks of benign breast tissue with associated clinical, epidemiological, and outcome information are limited, and pooling of our data and tissue samples will allow us to examine our hypotheses expeditiously. This molecular epidemiological study has translational potential since it may allow refinement of risk assessment models and facilitate the development of new approaches to the detection and clinical management of women at risk for breast cancer. Furthermore, establishment of our international, multi-disciplinary group will create a unique forum in which to undertake not only this study but also further investigations of the molecular pathogenesis of breast cancer.