Of all racial/ethnic groups, African Americans and Africans experience a disproportionate burden of premenopausalbreast cancer for reasons that remain unknown and understudied. The vast majority ofAfrican-Americans originated from West Africa, a region currently estimated to have a population of 200million persons, of whom more than 120 million is concentrated in Nigeria. In the post genome age,research focused on racial or ethnic group differences is less relevant in view of the dynamic interplaybetween genes and the environment. Rather, we believe studies should be focused on the individual,each with her unique genetic constitution and history of environmental exposures. We are in a uniqueposition to fill the huge knowledge gaps in the causes of breast cancer in populations of African ancestryby examining a large cohort of African American and Nigerian breast cancer cases. In ongoing workfunded through separate R01s, we are collecting comprehensive family and exposure history and haveestablished a large bio-specimen repository of cases and controls from Nigeria that will be invaluable forassessing the reasons why women of African ancestry develop earlier onset and pathologically moreaggressive breast cancer. This project aims at testing whether sequence variation in genes involved inthe metabolism of sex hormones and xenobiotics (including drugs) influences the risk to breast cancer.We will build on our previous efforts in this area that include large-scale SNP discovery studies guidedby comparative genomics analyses involving the UGT1A gene cluster and the CYP3A gene cluster.The goal of this SPORE proposal is to extend our studies and determine whether sequence variationin the UDP-glucuronosyltransferases 2B (UGT2B) family of genes influence the risk to breast cancer.Constructing genetic profiles that could be used to assess risk could also be used to individualizetherapy and will increase our understanding of the role of gene environment interactions in breastcancer etiology and treatment. Moreover, because these enzymes are important in the metabolism ofanticancer agents, the information obtained through these studies may help in dissecting the geneticbases of inter-individual variability in response to anticancer treatment and, ultimately, lead toindividualized therapy. This should ultimately lead to reduced breast cancer morbidity and mortalityand improved clinical outcomes for all women with breast cancer.
Our specific aims are:1) Perform are-sequencing survey of the UGT2B gene cluster based on comparative genomics analyses inethnically diverse population samples to select tag SNPs for association study; 2) Examine whetherpolymorphic variants of UGT2B genes are associated with breast cancer risk in women of Africandescent and 3) Examine whether UGT2B genes and environmental factors are associated with age atdiagnosis, tumor grade, and ER/PR staining.
Showing the most recent 10 out of 203 publications
