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

描述（由申请人提供）：尽管总体而言，欧洲-美国（EA）女性的乳腺癌发病率高于非洲-美国（AA）女性，但AA女性更可能在年轻时被诊断出，并且具有更具侵袭性的肿瘤，其特征在于更高的等级，更高的增殖指数，以及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这些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，对影响乳腺癌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子可以针对AA和EA女性中侵袭性乳腺癌的危险因素进行预防。为了研究这个问题，我们将进行两阶段设计研究。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份新鲜冷冻组织样本进行全基因组甲基化，以发现种族之间甲基化差异最大的基因，并区分高和低侵袭性疾病。将在参与正在进行的病例对照研究的女性组织中评估种族和侵袭性差异最大的组织，该研究旨在研究AA女性中早期/侵袭性乳腺癌的预测因子。使用Illumina GoldenGate分析，将评估来自500名AA和500名EA女性的组织，以确定各组之间的甲基化模式是否不同。我们还将确定甲基化是否与年轻、ER状态和“三阴性”肿瘤相关。最后，我们将研究叶酸和相关营养因素以及饮酒量在预测各组内甲基化模式中的潜在作用。这项研究的结果将提供关于侵袭性乳腺癌病因的极其重要的信息，并可能极大地阐明AA妇女中这种更致命的疾病形式的原因。由于甲基化可以逆转，因此对这些差异的研究可以确定预防和早期检测以及治疗的目标。

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.