Variation in Hormone and xenobiotic metabolizing enzyme genes and breast cancer

University Of Chicago, Chicago IL

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Abstract

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