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Molecular Epidemiology of Steroid Hormone Metabolism in Relation to Breast Cancer Risk in African Americans
Background: The increased risk of breast cancer to women with a family history of the disease supports a role for genetic and non-genetic factors that cluster in families. While the rare “highly penetrant” BRCA1 and BRCA2 genes account for a substantial proportion of families with many affected individuals and/or young ages at diagnosis, common “low penetrance” genes, such as those involved in steroid hormone metabolism, may act with other genetic and non-genetic exposures in the majority of breast cancer cases. Although associations of some of these loci with breast cancer have been found, the proportion of African American participants was generally quite low. As several breast cancer manifestations have a less favorable prognosis in African Americans than Caucasians, it is imperative that African Americans be adequately represented in studies. Objective/ Hypothesis: The associations with breast cancer risk of African American-specific or African American-predominant polymorphisms at steroid hormone metabolism loci will be assessed in a population-based case-control study. We hypothesize that associations with breast cancer will be found, which may differ from previous reports in Caucasians due to the specific alleles under investigation. Specific Aims: (1) To obtain DNA from 200 African American breast cancer patients (cases) and 200 unrelated controls, frequency matched to the cases for age, gender, and race, (2) to genotype cases and controls for specifically or predominantly African American polymorphisms at steroid hormone metabolism loci, and (3) to test for associations of these polymorphisms with breast cancer risk. Study Design: Most subjects will have already provided DNA through their participation in one of two recent studies conducted at our Cancer Registry. DNA will be genotyped using appropriate 5’-nuclease TaqMan or length polymorphism assays. Allele frequencies and associations with breast cancer risk will be assessed with chi-square and t-tests and logistic regression. Potential Outcomes and Benefits of the Research: This study will better inform our understanding of the distinct breast cancer manifestations in African Americans. Also, by identifying genotypes that may increase breast cancer risk in African Americans, it will improve our ability to target enhanced screening and chemopreventive efforts to susceptible individuals, reducing the public health burden of this serious disease.
Having a family history of breast cancer increases a woman’s risk of developing the disease, which suggests that shared familial factors contribute to breast cancer risk. Although the rare BRCA1 and BRCA2 genes play a major role in certain families where many members develop breast cancer, often at young ages, most women with breast cancer do not have alterations in these genes. Thus the majority of breast cancer may be associated with other more common genes that individually only slightly increase disease risk. Also, combinations of these genes, along with a woman’s medical history, may interact to further increase breast cancer risk. Such genes may include those that determine a woman’s level of exposure to steroid hormones, such as estrogen. A number of studies reported associations between these genes and breast cancer; however African Americans were generally underrepresented. Since several breast cancer features tend to be less favorable in African Americans than Caucasians, it is essential that African Americans be well represented in such studies. We hypothesize that alterations in genes that determine steroid hormone levels are associated with breast cancer risk and that these associations may vary by race as a function of the specific alterations under investigation. We have chosen to study African American-specific or African American-predominant alterations in genes that determine steroid hormone levels by comparing a representative sample of 200 African American women with breast cancer to a similar sample of 200 African American women without the disease. Most of these women have already recently donated a DNA sample for use in this study. We will determine the frequency of each genetic alteration in the two groups of women, as well as the strength of the association between each alteration and breast cancer risk. This study can provide a better understanding of the role of genes controlling steroid hormone levels in explaining the tendency for breast cancer to be a more aggressive disease with a less favorable prognosis in African Americans, compared to Caucasians. Furthermore, by identifying genes that may contribute to breast cancer risk in African Americans, it will enhance the ability to determine which individuals are genetically predisposed to the disease so that they may be offered improved screening and/or chemoprevention to reduce the public health burden of this serious disease.