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

描述（由申请人提供）：大多数乳腺癌病例涉及多个基因和环境因素的贡献。包括乳腺癌在内的几种癌症与低DNA修复能力（DRC）有关。大多数诱发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。本申请的目的是解决DNA修复基因子集中遗传遗传多态性在控制DRC水平和乳腺癌风险中的作用。我们的中心假设是，在维持DNA完整性的基因中，个体间的遗传变异参与决定DRC和乳腺癌的风险。在这项初步研究中，我们将专注于核苷酸切除修复（NER）途径基因。在具体目标#1中，我们将鉴定与DRC水平和乳腺癌风险相关的NER途径基因中的单核苷酸多态性（SNP）。为了实现这一目标，我们将比较一组已知DNA修复能力的乳腺癌患者和对照组的等位基因和基因型频率。我们将研究单个SNP位点，基因-基因相互作用和环境因素对SNP相关风险的影响。在特定目标#2下，我们将建立NER候选基因中拷贝数变异（CNV）在乳腺癌遗传易感性中的作用。我们将确定包括NER基因的区域中的拷贝数变异，并将CNV数据与DRC和乳腺癌表型相关联。该MBRS-SC2应用提出了一种综合和创新的策略，以揭示SNP和CNV遗传因子对DRC表型和乳腺癌风险的作用。此外，它针对的是西班牙裔人口，这在大多数遗传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，拟议的项目预计将对PI的职业生涯产生积极影响，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作为管理波多黎各乳腺癌遗传风险的专家来实现研究独立。Dutil博士在分子遗传学方面受过良好的培训，并由一个强大的多学科团队包围：Matta博士（PSM）是DNA修复专家，将提供超过570名参与者的研究人群; Lizardi博士（耶鲁大学）是基因组学技术和全基因组重排图谱的专家; Rebecca Sutphen博士（莫菲特癌症中心）将提供TagSNP选择的指导; Manuel Bayona博士（PSM）是生物统计学家和流行病学家，将监督统计分析。 公共卫生相关性：据估计，美国约有300万妇女患有乳腺癌。生活方式和遗传因素被认为会增加某些女性患乳腺癌的风险，但我们对这些基因知之甚少。关于某些少数民族人口，如波多黎各的西班牙裔人，可获得的信息更少。研究表明，那些接受过乳腺癌风险增加教育的人更有可能参与降低风险的行为和早期检测策略，如每月自我乳房检查，医生访问，乳房X光检查和乳房MRI筛查。因此，通过确定使一些女性更容易患乳腺癌的基因，我们希望改善早期检测和预防策略，并提供适合每个人群的乳腺癌风险的临床管理。

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.