Variation in Hormone and xenobiotic metabolizing enzyme genes and breast cancer

在所有种族/族裔群体中，非裔美国人和非洲人经历了不成比例的绝经前负担

Of all racial/ethnic groups, African Americans and Africans experience a disproportionate burden of premenopausal breast cancer for reasons that remain unknown and understudied. The vast majority of African-Americans originated from West Africa, a region currently estimated to have a population of 200 million 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 interplay between 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 unique position to fill the huge knowledge gaps in the causes of breast cancer in populations of African ancestry by examining a large cohort of African American and Nigerian breast cancer cases. In ongoing work funded through separate R01s, we are collecting comprehensive family and exposure history and have established a large bio-specimen repository of cases and controls from Nigeria that will be invaluable for assessing the reasons why women of African ancestry develop earlier onset and pathologically more aggressive breast cancer. This project aims at testing whether sequence variation in genes involved in the 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 guided by 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 variation in 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 individualize therapy and will increase our understanding of the role of gene environment interactions in breast cancer etiology and treatment. Moreover, because these enzymes are important in the metabolism of anticancer agents, the information obtained through these studies may help in dissecting the genetic bases of inter-individual variability in response to anticancer treatment and, ultimately, lead to individualized therapy. This should ultimately lead to reduced breast cancer morbidity and mortality and improved clinical outcomes for all women with breast cancer. Our specific aims are:1) Perform a re-sequencing survey of the UGT2B gene cluster based on comparative genomics analyses in ethnically diverse population samples to select tag SNPs for association study; 2) Examine whether polymorphic variants of UGT2B genes are associated with breast cancer risk in women of African descent and 3) Examine whether UGT2B genes and environmental factors are associated with age at diagnosis, tumor grade, and ER/PR staining.