African Americans and Africans experience a disproportionate burden of pre-menopausal breast cancer for reasons that remain unknown. The identification of persons carrying breast cancer susceptibility genes is a promising approach to understanding the etiology of the disease and developing more effective early detection and prevention strategies. With the cloning of BRCA1 and BRCA2 genes, there is an urgent need to identify mutations among different ethnic populations in order to study mutation spectrum, age-specific penetrance, risks of other cancers, epidemiological risk factors, and effects of modifier genes for mutation carriers. It is more than 6 years since BRCA1was cloned and yet, there is little information available about the role of BRCA1and BRCA2 for ethnic groups other than Caucasians of Northern European ancestry. Our proposal aims to narrow the knowledge gap by examining a large cohort of African American and African breast cancer cases. We propose to ascertain a total of 1000 Nigerian women diagnosed with breast cancer at, or before, age 65, and 1000 controls. All women under the age of 45 and women with a family history of breast or ovarian cancer, or bilateral breast cancer will be screened for BRCA1 and BRCA2 mutations. The incidence and spectrum of mutations identified in these cases will be compared to that previously reported in Caucasian women and to that obtained in 360 African American women from Northern California who are participating in the Cooperative Family Registry for Breast Cancer Studies (CFRBCS). Detailed family cancer history and exposure information will be collected on each participant to determine whether differences exist in exposure history and clustering of breast and other cancers in the families of women with breast cancer, in Nigeria and the United States. Penetrance of BRCA mutations will be estimated for African American and Nigerian kindreds that are segregating a deleterious mutation. UGT1A1 enzyme is one of the major UGT involved in estradiol glucunonidation and also constitutes a major detoxification pathway for toxic or carcinogenic compounds. We have found that populations of African Origin harbor four different alleles of UGT1A1 while non-African populations appear to have only two alleles. In addition, alleles associated with lower gene expression levels reach the highest frequency in populations of sub-Saharan African. Using the resources of the CFRBCS and those collected in this study, the association between single nucleotide polymorphisms and in a number of the genes in the UGTIA cluster and breast cancer will be assessed in a Nigerian case-control study and an African-American case-control study. In addition, UGTIA polymorphisms will be examined as a potential modifies of BRCA1 or BRCA2 cancer risk The accurate definition of genetic risks for young Black women will eventually lead to more accurate clinical risk assessment and the development of targeted prevention, early detection and treatment strategies that should ultimately lead to reduced breast cancer mortality and improved clinical outcomes in young women of African ancestry.

R01CA089085

2002-09-01

2008-08-31