Molecular epidemiology studies on the role of DNA repair breast cancer

描述（由申请人提供）：癌症是美国和波多黎各（PR）的第二大死亡原因。乳腺癌（BC）是PR中女性最常见的癌症，DNA修复能力（DRC）是保护基因组完整性和稳定性的关键系统。本病例对照研究的总体目标是检查低DRC是否是乳腺癌的预测因子，并确定与DNA修复能力相关的基因表达是否随年龄和BC亚型而变化。由于年龄是癌症最重要的风险因素之一，DRC随着年龄的增长而下降，因此该项目将确定最近发现的与DRC丢失相关的关键基因。这将通过追求以下具体目标来实现：1）测试DRC是否可以用作不同年龄组妇女BC风险的预测因子。在当前周期中收集的数据显示，与对照组（n=479）相比，PR伴BC的女性（n=283）的年龄调整DRC在统计学上（p<0.001）显著降低（56%）。2)以确定与DRC的各种表型相关的DNA修复基因的表达是否作为年龄的函数而变化。据推测，BC女性的关键DNA修复基因的表达随着年龄的变化而改变。3)研究乳腺癌的主要流行病学危险因素及其与妇女DRC的关系。4)发展表观遗传学领域的科学专业知识，并在PI实验室的癌症研究中利用这些新发现的工具。将使用LUC质粒的宿主细胞再活化试验比较BC女性和无癌症对照女性的淋巴细胞的DRC。数据将按DNA修复水平和年龄组分层。将使用粗比值比和多元logistic回归校正比值比作为BC、DRC和其他流行病学因素之间相关性的指标，同时校正所有混杂因素。将评价肿瘤和正常组织样本的DNA修复基因差异表达。本研究将确定与BC相关的新的基因组、表观遗传和表型性状，这将为更准确地预测BC风险提供一种手段。 公共卫生相关性：乳腺癌是波多黎各妇女的头号癌症杀手，老龄化是最重要的风险因素之一。这项研究的重点是检查低DNA修复能力是否是乳腺癌的预测因子，并确定与之相关的基因表达是否随年龄而变化。这项研究包括研究乳腺癌的关键基因组、表观遗传和流行病学风险因素及其与妇女DNA修复能力的关系。这些结果已经提供了有价值的信息，即哪些特定的DNA修复基因被解除管制，并与我们发现的影响BC进展的DNA修复能力缺陷有关，以及对BC表型-基因型关系的独特见解。这项研究还将为PI和学生提供机会，以发展表观遗传学领域的科学专业知识，用于未来的癌症研究。该项目的成果将提供信息和新方法，以确定乳腺癌高风险妇女和乳腺癌筛查的新方法。

DESCRIPTION (provided by applicant): Cancer is the second leading cause of mortality in the USA and Puerto Rico (PR). Breast cancer (BC) is the most common cancer in women in PR. The DNA repair capacity (DRC) is a critical system aimed at protecting the integrity and stability of the genome. The overall aim of this incident case-control study is to examine whether a low DRC is a predictor of breast cancer and to identify whether the expression of genes that are associated with DNA repair capacity vary as a function of age and subtype of BC. Because age is one of the most important risk factor for cancer and DRC declines with age, this project will identify recently discovered critical genes associated with the loss of DRC. This will be achieved by pursuing the following Specific Aims: 1) to test whether DRC can be utilized as a predictor for BC risk in women of different age groups. Data gathered during the current cycle have shown that women (n=283) in PR with BC have a statistically (p<0.001) significant reduction (56%) in age-adjusted DRC compared to controls (n=479). 2) to identify whether the expression of DNA repair genes that are associated with various phenotypes of DRC vary as a function of age. It is hypothesized that women with BC have an altered expression of key DNA repair genes as a function of age. 3) To study key epidemiological risk factors for breast cancer and their association with DRC in women. 4) To develop scientific expertise in the area of epigenetics and to utilize these newfound tools in cancer studies in the laboratory of the PI. Lymphocytes of women with BC and cancer-free controls will be compared for their DRC using the host-cell reactivation assay with a LUC plasmid. Data will be stratified by DNA repair level and age group. The crude and the multiple logistic regression adjusted odds ratios will be used as measures of association between BC, DRC, and other epidemiological factors, adjusting for all confounders simultaneously. Tumor and normal tissue samples will be evaluated for the differential expression of DNA repair genes. The novel genomic, epigenetic and phenotypic traits associated with BC that will be identified in this study will provide a means to more accurately predict BC risk. PUBLIC HEALTH RELEVANCE: Breast cancer is the number one cancer killer of women in Puerto Rico, and ageing is one of the most important risk factors. The focus of this study is to examine whether a low DNA repair capacity is a predictor of breast cancer and identify whether the expression of genes that are associated with it vary as a function of age. This research includes the study of key genomic, epigenetic and epidemiological risk factors for breast cancer and their association with DNA repair capacity in women. The results are already providing valuable information on which specific DNA repair genes are deregulated and associated with the defects we have found in DNA repair capacity impacting BC progression, and on unique insights into the BC phenotype-genotype relationship. This study will also provide the opportunity to the PI and students to develop scientific expertise in the area of epigenetics to use in future cancer studies. The results of this project will provide information and new methodologies to identify women with high risk of breast cancer and new ways for breast cancer screening.