Inherited genetic factors in breast cancer predisposition and tumor presentation

描述（由申请人提供）：乳腺癌是一个发病率和死亡率高的主要公共卫生问题。遗传因素已被证明影响乳腺癌的易感性和预后。乳腺癌的遗传基础也可能因病理亚型而异。我们的长期目标是了解基因变异如何调节乳腺癌的风险和肿瘤特征。核苷酸切除修复（NER）途径专门修复各种DNA螺旋畸变。与非癌症对照组相比，波多黎各乳腺癌病例的DNA修复能力（DRC）水平显著下降，DNA修复能力（DRC）水平主要衡量NER的活性。在具体目标#1中，我们将确定与乳腺癌风险相关的NER基因区域的拷贝数变异。我们将首先使用靶向阵列比较杂交（CGH）筛选NER通路基因是否存在CNVs。接下来，我们将评估在乳腺癌病例对照人群中确定的CNVs的相关性。在具体目标#2中，我们建议定性地（基因结构）或定量地（基因表达水平）确定NER途径CNVs对基因表达的功能意义。我们将对鉴定出CNVs的NER基因通路基因进行靶向RNA测序（RNA- Seq）。我们将搜索CNV相关的基因表达变化、剪接变异和融合转录本。具体目标#3依赖于我们的初步数据显示，在波多黎各妇女中，非洲血统与ER-PR-肿瘤的高风险相关。在这个目的中，我们将通过混合连锁不平衡作图来确定乳腺癌患者对激素受体阴性肿瘤易感性的基因组区域。这种方法利用种群间基因变异频率的差异来发现致病基因。该应用程序提出了一种综合和创新的策略，以提高我们对遗传学在乳腺癌中的作用的理解，它针对的是西班牙裔人群，这在遗传学研究中往往代表性不足。随着越来越多的常见基因变异的发现，可以累积识别风险分布的极端，人们可以开始设想通过平衡风险水平和适当的风险降低干预来实现乳腺癌的“个性化预防”。这项研究的结果可以为实现这一目标做出重要贡献。拟议的项目预期将对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，从而获得r型资金。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博士是DNA修复专家，将提供超过1,084名参与者的研究人群；Massey博士是应用于基因组数据的生物信息学专家；Schabath博士是一名癌症遗传流行病学家；Ziv博士是乳腺癌混合图谱领域的领军人物。

DESCRIPTION (provided by applicant): Breast cancer is a major public health problem with high incidence and mortality rates. Inherited genetic factors have been shown to influence susceptibility to breast cancer and prognosis. The genetic basis to breast cancer may also differ by pathology subtypes. Our long-term objective is to understand how genetic variations modulate breast cancer risk and tumor characteristics. The nucleotide excision repair (NER) pathway and specializes in repairing a wide variety of DNA helix distortions. Significant decreases in DNA repair capacity (DRC) levels, which measures mostly the activity of the NER, have been observed in breast cancer cases from Puerto Rico when compared to non-cancer controls. In specific aim#1, we will identify copy number variants in the NER gene regions that are associated with breast cancer risk. We will first screening the NER pathway genes for the presence of CNVs using targeted array comparative hybridization (CGH). Next, we will assess the association of the identified CNVs in a breast cancer case-control population. In specific aim#2, we propose to determine the functional significance of the NER pathway CNVs on gene expression qualitatively (gene structure) or quantitatively (gene expression levels). We will perform targeted RNA-sequencing (RNA- Seq) on the NER gene pathway genes in which CNVs were identified. We will search for CNV associated gene expression changes, splice variants, and fusion transcripts. Specific aim#3 relies on our preliminary data showing that in Puerto Rican women, African ancestry is associated with higher risk of ER-PR- tumors. In this aim, we will identify the genomic regions underlying susceptibility to hormonal receptor-negative tumors in breast cancer patients using mapping by admixture linkage disequilibrium. This method takes advantage of the differences in the frequency of genetic variants between populations to uncover disease-causing genes. This application proposes an integrated and innovative strategy to improve our understanding of the role of genetics in breast cancer and it targets a Hispanic population, which is often underrepresented in genetic studies. With increasing discovery of common genetic variants that may cumulatively identify the extremes of the risk distribution, one can begin to envision "personalized prevention" of breast cancer by balancing the level of risk with an appropriate risk reduction intervention. The results from the proposed study can contribute importantly to this goal. 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 that will lead to R-type funding. Dr. Dutil is well trained in molecular genetics and i surrounded by a strong multidisciplinary team: Dr. Matta is an expert in DNA repair and will provide the study population of over 1,084 participants; Dr. Massey is an expert in bioinformatics applied to genomic data; Dr. Schabath is a cancer genetic epidemiologist; and Dr Ziv is a leader in the field of breast cancer admixture mapping.