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）第二大死亡原因。乳腺癌（BC）是PR女性中最常见的癌症，DNA修复能力（DRC）是一个关键系统，旨在保护基因组的完整性和稳定性。该事件病例对照研究的总体目的是检查低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亚型的变化而变化。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，该项目将确定最近发现的与DRC损失相关的关键基因。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。当前周期收集的数据显示，与对照组（n=479）相比，PR合并BC的女性（n=283）年龄调整后的DRC（56%）有统计学意义（p<0.001）显著降低。2)确定与DRC各种表型相关的DNA修复基因的表达是否随年龄而变化。据推测，BC患者的关键DNA修复基因的表达随年龄的变化而改变。3)研究女性乳腺癌的主要流行病学危险因素及其与DRC的关系。4)发展表观遗传学领域的科学专业知识，并将这些新发现的工具用于PI实验室的癌症研究。将使用带有LUC质粒的宿主细胞再激活试验比较患有BC和无癌症对照的女性淋巴细胞的DRC。数据将按DNA修复水平和年龄组分层。粗比值比和多重logistic回归校正比值比将被用作BC、DRC和其他流行病学因素之间关联的度量，同时对所有混杂因素进行校正。肿瘤和正常组织样本将被评估DNA修复基因的差异表达。本研究将发现与BC相关的新的基因组、表观遗传和表型特征，这将为更准确地预测BC风险提供一种手段。

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.