DNA Methylation: a Mechanism for Aggressive Breast Cancer in African-American Wom

描述（由申请人提供）：尽管欧裔美国人（EA）女性的乳腺癌发病率总体上高于非裔美国人（AA）女性，但AA女性更有可能在更年轻时被诊断出来，并且具有更强的侵袭性，其特征是更高的分级，更高的增殖指数，缺乏雌激素和孕激素受体的表达。乳腺癌生物学和发病年龄的种族差异的原因尚不清楚，但差异基因甲基化可能会影响肿瘤生物学的这些差异。此外，我们对乳腺癌中影响基因甲基化的因素知之甚少。深入了解基因甲基化的预测因素可以针对AA和EA女性侵袭性乳腺癌的危险因素进行预防。为了调查这个问题，我们将进行两个阶段的设计研究。在第一个发现阶段，我们将对来自100名AA和100名EA乳腺癌患者的100个新鲜冷冻组织样本进行全基因组甲基化，以发现种族间甲基化差异最大的基因，以及区分高侵袭性和低侵袭性疾病的基因。在一项正在进行的病例对照研究中，将对那些种族和侵袭性差异最大的女性的组织进行评估，该研究旨在调查AA女性早期/侵袭性乳腺癌的预测因素。使用Illumina GoldenGate Assay，将对500名AA和500名EA女性的组织进行评估，以确定甲基化模式在两组之间是否存在差异。我们还将确定甲基化是否与年轻、ER状态和“三阴性”肿瘤有关。最后，我们将研究叶酸和相关营养因素以及酒精摄入量在预测各组甲基化模式中的潜在作用。这项研究的结果将为侵袭性乳腺癌的病因提供极其重要的信息，并可能极大地阐明这种在AA女性中更致命的疾病形式的原因。由于甲基化可以逆转，对这些差异的研究可以确定预防和早期发现以及治疗的目标。

DESCRIPTION (provided by applicant): Although European-American (EA) women, overall, have higher incidence of breast cancer than African-American (AA) women, AA women are more likely to be diagnosed at a younger age, and to have more aggressive tumors, characterized by higher grade, higher proliferative indices, and lack of expression of estrogen and progesterone receptors. The reasons for these racial differences in breast cancer biology and age at onset are unknown, but it is possible that differential gene methylation could affect these differences in tumor biology. Furthermore, little is known regarding factors that affect gene methylation in breast cancer. Insight into predictors of gene methylation could target risk factors for aggressive breast cancer in both AA and EA women for prevention. To investigate this question, we will perform a two stage design study. In the first discovery stage, we will perform genome-wide methylation on a sample of 100 freshly frozen tissues from 100 AA and 100 EA breast cancer patients for discovery of genes that are most differentially methylated between the races and that differentiate between high and low aggressive disease. Those most significantly different by race and aggressiveness will be assessed in tissues from women participating in an on-going case-control study designed to investigate predictors of early/aggressive breast cancer in AA women. Using the Illumina GoldenGate Assay, tissues from 500 AA and 500 EA women will be evaluated to determine if methylation patterns differ between the groups. We will also determine if methylation is associated with younger age, ER status and ''triple negative' tumors. Finally, we will investigate the potential role of folate and related nutritional factors, as well as alcohol consumption in predicting methylation patterns within each group. Results from this study will provide extremely important information regarding the etiology of aggressive breast cancers, and may greatly elucidate reasons for this more lethal form of disease among AA women. Because methylation can be reversed, interrogation of these differences could identify targets for prevention and early detection, as well as for treatment. Public Health Relevance: This project will identify genes that are differentially methylated between African- American and European-American women and potential predictors of methylation patterns. As such, it could provide insight into factors related to the aggressive breast cancers observed in African-American women. Because methylation is reversible, it may also provide new directions for prevention and therapeutics.