Factors associated with variability in DNA repair capacity in their effect on bre

与 DNA 修复能力变异相关的因素对布雷的影响

• 批准号: 9107822
• 负责人: Jaime L Matta
• 金额: $ 36.7万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107822
• 关键词: Alleles; Ancillary Study; Biological Markers; Blood; Blood Tests; Blood specimen; Breast; Breast Cancer Patient; Breast Cancer Prevention; Breast Cancer Risk Factor; Breast Carcinogenesis; Cancer Center; Cancer Research Infrastructure; Candidate Disease Gene; Cohort Studies; Complex; DNA Repair; DNA Repair Gene; DNA Repair Pathway; Development; Diagnostic; Disease; Distant; ERBB2 gene; Environmental Risk Factor; Epidemiological Factors; Epidemiology; Epigenetic Process; Estrogen Receptors; Etiology; FOLH1 gene; Genes; Genetic; Goals; Health; Hereditary Breast Carcinoma; Hormone Receptor; Human; Impairment; Individual; Island; Knowledge; Lead; Legal patent; Lymphocyte; Malignant Neoplasms; Mammary Neoplasms; Methods; Methylation; MicroRNAs; Nucleotide Excision Repair; Participant; Pathway interactions; Patients; Postmenopause; Prevention; Process; Progesterone Receptors; Prognostic Marker; Progress Reports; Publishing; Puerto Rican; Recording of previous events; Recruitment Activity; Recurrence; Research; Risk; Risk Estimate; Risk Factors; Risk Marker; Sampling; Side; Statistical Methods; Testing; Woman; Women Status; Work; base; cancer recurrence; cancer risk; cancer therapy; cancer type; carcinogenesis; clinically relevant; cohort; doctoral student; erbB-2 Receptor; genetic risk factor; genome integrity; high risk; human DNA; improved; malignant breast neoplasm; methylation pattern; outcome forecast; predictive marker; programs; promoter; receptor; screening; specific biomarkers

DESCRIPTION (provided by applicant): Breast cancer is a complex disease that is caused by multiple factors. Deficits in DNA repair capacity (DRC) are known to cause certain familial breast cancers, and dysregulation of DRC develops with progressive carcinogenesis. However, the effect of DRC on carcinogenesis of sporadic breast tumors has not been well characterized-and the factors associated with DRC variability are still poorly understood. DNA repair is integral to maintaining genomic integrity, and carcinogenesis occurs when efficient, effective DNA repair is impaired. Thus, we believe that studying DRC in women without and with breast cancer (BC) will provide critical new information to help predict breast cancer risk and its risk of recurrence Identifying phenotypic, epigenetic, and epidemiological factors that can be used as diagnostic or prognostic indicators holds great value for improving human health in relation to breast cancer prevention and therapy. We have shown that a wide range of DRC variability exists in the large cohort of women we have been studying since 2006, which alludes to DRC being influenced by genetic, environmental, and epigenetic factors. Identifying what causes that variability will bring us closer to finding new, clinically relevant biomarkers for breast cancer. To that end, we hypothesize that (1) low DRC is a predictor of breast cancer risk and recurrence, and that (2) certain genetic and epigenetic factors directly influence DRC variability. Our three aims will test these hypotheses, with the ultimate goal of uncovering new information that can expand the repertoire of predictive and prognostic biomarkers for breast cancer through the use of simple blood tests. Our first aim will test the hypothesis that a low DRC is a predictor of breast cancer risk and recurrence by utilizing the cohort of 1,083 women recruited in our ongoing study. We will do this by utilizing a method that tests for a particular DNA repair pathway (the Nucleotide Excision Repair pathway) that has been shown to be deficient in women with BC. The second aim evaluates the relationship of DRC and hormone receptor status, which, if validated, would represent a genetic influence on BC. We hypothesize that BC patients with HER2/neu or progesterone receptors are more likely to have a low DRC than patients with estrogen receptors. We also will explore whether BC patients with double- and triple-negative receptors have greater odds of a low DRC. In the third aim, we will study two epigenetic mechanisms that may be partly responsible for the DRC impairment that we have found in women with BC. Using a candidate gene approach, we will study (1) methylation patterns of certain DNA repair gene promoters and (2) levels of expression of selected miRNAs. We hypothesize that abnormal methylation of gene promoters and altered expression of miRNAs contributes to a low DRC (and thus, increases the risk of developing primary or recurrent BC). As a side benefit to this research, all these tests are done on blood samples. If our hypotheses are correct, our work could lead to new, simple, non-invasive screening tests for breast cancer.

描述（申请人提供）：乳腺癌是一种由多种因素引起的复杂疾病。已知DNA修复能力（DRC）的缺陷会导致某些家族性乳腺癌，DRC的失调会随着进行性癌变而发展。然而，DRC对散发性乳腺肿瘤发生的影响还没有得到很好的表征，与DRC变异性相关的因素仍然知之甚少。DNA修复不可或缺 维持基因组的完整性，当有效的DNA修复受损时，就会发生癌变。因此，我们相信，研究DRC在妇女没有和乳腺癌（BC）将提供关键的新信息，以帮助预测乳腺癌的风险和复发的风险确定表型，表观遗传和流行病学因素，可用作诊断或预后指标具有很大的价值，改善人类健康的乳腺癌预防和治疗。我们已经证明，自2006年以来，我们一直在研究的大型女性队列中存在广泛的DRC变异性，这暗示DRC受到遗传，环境和表观遗传因素的影响。确定可变性会带来什么原因 我们更接近于发现新的，临床相关的乳腺癌生物标志物。为此，我们假设（1）低DRC是乳腺癌风险和复发的预测因子，（2）某些遗传和表观遗传因素直接影响DRC变异性。我们的三个目标将检验 这些假设的最终目标是发现新的信息，可以通过使用简单的血液测试来扩展乳腺癌的预测和预后生物标志物的库。我们的第一个目标是通过利用我们正在进行的研究中招募的1,083名妇女的队列来验证低DRC是乳腺癌风险和复发的预测因子的假设。我们将通过利用一种方法来测试特定的DNA修复途径（核苷酸切除修复途径），该途径已被证明在BC女性中存在缺陷。第二个目标是评估DRC和激素受体状态的关系，如果得到验证，将代表对BC的遗传影响。我们假设，与雌激素受体的患者相比，HER 2/neu或孕激素受体的BC患者更有可能具有低DRC。我们还将探讨双阴性和三阴性受体的BC患者是否具有更大的低DRC几率。在第三个目标中，我们将研究两个表观遗传机制，这可能是部分负责DRC的损害，我们发现在妇女与BC。使用候选基因方法，我们将研究（1）某些DNA修复基因启动子的甲基化模式和（2）选定的miRNA的表达水平。我们假设基因启动子的异常甲基化和miRNA表达的改变有助于低DRC（从而增加发生原发性或复发性BC的风险）。作为这项研究的附带好处，所有这些测试都是在血液样本上进行的。如果我们的假设是正确的，我们的工作可能会导致新的，简单的，非侵入性的乳腺癌筛查测试。