Defining breast cancer risk: the role of genetic variations in DNA repair genes

描述（申请人提供）：大多数乳腺癌病例涉及多种基因和环境因素的共同作用。包括乳腺癌在内的几种癌症与低DNA修复能力（DRC）有关。大多数易患乳腺癌的基因仍然未知，乳腺癌患者低DRC的原因也知之甚少。本应用程序的目的是解决DNA修复基因子集中遗传基因多态性在控制DRC水平和乳腺癌风险中的作用。我们的中心假设是，参与维持DNA完整性的基因的个体间遗传变异参与了DRC和乳腺癌风险的决定。在这项初步研究中，我们将重点研究核苷酸切除修复（NER）途径基因。在具体目标#1中，我们将确定与DRC水平和乳腺癌风险相关的NER通路基因中的单核苷酸多态性（snp）。为了实现这一目标，我们将比较一组乳腺癌患者和DNA修复能力已知的对照组的等位基因和基因型频率。我们将研究单SNP位点、基因-基因相互作用以及环境因素对SNP相关风险的影响。在特定目标#2下，我们将确定NER候选基因中的拷贝数变异（CNVs）在乳腺癌遗传易感性中的作用。我们将确定包含NER基因的区域的拷贝数变化，并将CNV数据与DRC和乳腺癌表型相关联。这项MBRS-SC2应用提出了一种整合的创新策略，以揭示SNP和CNV遗传因素在DRC表型和乳腺癌风险中的作用。此外，它针对的是西班牙裔人群，这在大多数基因研究中往往代表性不足。我们的研究结果有望改善高危女性乳腺癌的预防和检测。此外，拟议的项目预期将对项目专员的职业生涯产生积极影响，因为它将为编写高质量的手稿提供基础，并为准备竞争性赠款申请提供初步数据。通过这个为期三年的计划，Dutil博士打算通过建立自己在波多黎各管理乳腺癌遗传风险的专家来实现研究独立性。Dutil博士在分子遗传学方面训练有素，并拥有一支强大的多学科团队：Matta博士（PSM）是DNA修复方面的专家，将为570多名参与者提供研究人群；Lizardi博士（耶鲁大学）是基因组学技术和全基因组重排制图方面的专家；Rebecca Sutphen博士（Moffitt癌症中心）将提供标签snp选择的指导；Manuel Bayona博士（PSM）是一位生物统计学家和流行病学家，他将监督统计分析。

DESCRIPTION (provided by applicant): The majority of breast cancer cases involve the contribution of multiple genes and environmental factors. Several cancers, including breast cancer, have been associated with low DNA repair capacity (DRC). Most of the genes predisposing to breast cancer remain unknown, and the causes of the low DRC in breast cancer patients are poorly understood. The objective of this application is to address the role of inherited genetic polymorphisms in a subset of DNA repair genes in controlling DRC levels and risk of breast cancer. Our central hypothesis is that inter-individual genetic variations in the genes involved in the maintenance of DNA integrity participate in determining DRC and breast cancer risk. In this pilot study, we will focus on the Nucleotide Excision Repair (NER) pathway genes. In specific aim #1, we will identify single nucleotide polymorphisms (SNPs) in the NER pathway genes that are associated with DRC levels and breast cancer risk. To achieve this goal, we will compare allelic and genotype frequencies in a group of breast cancer patients and controls for which the DNA repair capacity is known. We will investigate single SNP loci, gene-gene interactions and the effect of environmental factors on the SNP associated risk. Under specific aim#2, we will establish the role of Copy Number Variations (CNVs) in NER candidate genes in genetic susceptibility to breast cancer. We will identify copy number variations in regions encompassing NER genes and correlate CNV data with the DRC and breast cancer phenotypes. This MBRS-SC2 application proposes an integrated and innovative strategy to unveil the role of SNP and CNV genetic factors on the DRC phenotype and the risk of breast cancer. Furthermore, it targets a Hispanic population, which is often underrepresented in most genetic studies. Our findings are expected to improve prevention and detection of breast cancer in at risk women. In addition, the proposed project is expected to have a positive impact on the PI's career by providing the basis for the preparation of high quality manuscripts and by providing preliminary data for the preparation of competitive grant applications. Through this three year program, Dr. Dutil intends to achieve research independence by establishing herself as an expert in managing the genetic risk for breast cancer in Puerto Rico. Dr. Dutil is well trained in molecular genetics and is surrounded by a strong multidisciplinary team: Dr. Matta (PSM) is an expert in DNA repair and will provide the study population of over 570 participants; Dr. Lizardi (Yale University) is an expert in genomics technologies and whole genome rearrangements mapping; Dr Rebecca Sutphen (Moffitt Cancer Center) will provide guidance in TagSNP selection; Dr. Manuel Bayona (PSM) is a biostatistician and epidemiologist who will oversee statistical analyses. PUBLIC HEALTH RELEVANCE: It is estimated that approximately 3 million women in the U.S. are living with breast cancer. Lifestyle and inherited genetic factors are believed to increase the risk that certain women develop breast cancer, but we know very little about these genes. Even less information is available for certain minority population, such as the Hispanics of Puerto Rico. Research has shown that those who are educated about their increased risk of breast cancer are more likely to engage in risk-reducing behaviors and early detection strategies such as monthly self-breast exam, physician visits, mammography and breast MRI screening. Therefore, by identifying the genes that make some women more at risk of developing breast cancer, we expect to improve early detection and prevention strategies, and provide a clinical management of breast cancer risk that is adapted to each population.