Epigenetic Modifiers of Breast Cancer Risk

描述(申请人提供)：乳腺癌(BC)是一种复杂的疾病，既有遗传原因，也有环境原因，是女性癌症死亡的第二大原因。大多数患乳腺癌的妇女(约70%)没有已知的家族史或明显的危险因素。其余30%的病例倾向于聚集在家族中，其中5%-7%的病例可通过BRCA1和BRCA2突变遗传，这是目前可用于乳腺癌的唯一基因检测。最近对乳腺导管上皮细胞和肿瘤组织的分子研究表明，存在一些DNA修复和肿瘤控制基因，这些基因的表达通过DNA甲基化有效地关闭或沉默为功能蛋白。假设乳腺上皮细胞中沉默的肿瘤控制基因的存在可能预示着具有这种分子修饰的女性最终发展为BC。这项研究的具体目的是：1)在患乳腺癌的高危女性队列中识别从乳腺肿瘤组织和周围健康乳腺组织分离的DNA中甲基化抑制的肿瘤控制基因，与患乳腺癌的平均风险女性的病例匹配对照队列进行比较；2)确定家庭和个人因素对乳腺癌预后的预测作用，如乳腺癌病史、发病年龄、产次、月经初潮年龄、既往乳腺活检、内源性和外源性激素暴露、筛查史和BRCA突变状态。这项研究对改进风险评估有意义，并最终可能在有关筛查和降低风险的预防措施(如降低风险的乳房切除术和化学预防)的决策过程中帮助女性。

DESCRIPTION (provided by applicant): Breast cancer (BC) is a complex disease with both genetic and environmental causes, and is the second leading cause of cancer death in women. Most women who develop breast cancer (approximately 70%) have no known family history or obvious risk factors. The remaining 30% of cases tend to aggregate in families, and 5-7% of these are heritable through BRCA1 and BRCA2 mutations, the only gene tests currently available for breast cancer. Recent molecular studies of breast ductal epithelial cells and tumor tissue have demonstrated the presence of several DNA repair and tumor control genes whose expression into functional proteins is effectively shut down or silenced via DNA methylation. It is hypothesized that the presence of silenced tumor control genes in breast epithelial cells may presage the eventual development of BC in women with such molecular modifications. The specific aims of this research are: 1) to identify methylation suppressed tumor control genes in DNA isolated from breast tumor tissue and surrounding healthy breast tissue in a cohort of women at high risk for BC, as compared to a case-matched control cohort of women at average risk for BC, and 2) to determine the predictive contributions of family and personal factors on breast cancer outcome, such as a history of BC, age-of-onset, parity, age at menarche, previous breast biopsies, endogenous and exogenous hormone exposure, screening history, and BRCA mutation status. This research has implications for improving risk assessment, and may ultimately aid women in the decision-making process regarding screening and risk reduction prophylactic measures such as risk reduction mastectomy and chemoprevention.