Inherited genetic factors in breast cancer predisposition and tumor presentation

描述(申请人提供)：乳腺癌是一个主要的公共卫生问题，发病率和死亡率都很高。遗传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不同而不同。我们的长期目标是了解基因变异如何调节乳腺癌风险和肿瘤特征。核苷酸切除修复(NER)途径，专门修复各种DNA螺旋扭曲。与非癌症对照组相比，波多黎各乳腺癌患者的DNA修复能力(DRC)水平显著下降，DRC主要衡量NER的活性。在特定的目标#1中，我们将确定NER基因区域中与乳腺癌风险相关的拷贝数变异。我们将首先使用靶向阵列比较杂交(CGH)来筛选NER途径基因以检测CNV的存在。接下来，我们将评估乳腺癌病例对照人群中已识别的CNV的相关性。在特定的目标#2中，我们建议定性(基因结构)或定量(基因表达水平)确定NER途径CNV对基因表达的功能意义。我们将对发现CNV的NER基因途径基因进行靶向RNA测序(RNA-Seq)。我们将寻找CNV相关基因的表达变化、剪接变体和融合转录本。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，非洲血统与更高的ER-PR-肿瘤风险相关。在这个目标中，我们将使用混合连锁不平衡作图来确定乳腺癌患者激素受体阴性肿瘤易感性的基因组区域。这种方法利用不同种群之间基因变异频率的差异来发现致病基因。这项应用提出了一种整合和创新的战略，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口，而这一群体在遗传学研究中往往被低估。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情况，人们可以开始设想通过平衡风险水平和适当的降低风险干预措施来对乳腺癌进行“个性化预防”。拟议研究的结果可以对这一目标作出重要贡献。预计拟议的项目将为编写高质量的手稿提供基础，从而为非政府组织的职业生涯带来积极影响，这些手稿将导致R型资助。杜蒂尔博士在分子遗传学方面训练有素，我身边有一支强大的多学科团队：马塔博士是DNA修复方面的专家，将为超过1084名参与者提供研究；梅西博士是应用于基因组数据的生物信息学专家；沙巴斯博士是癌症遗传流行病学家；齐夫博士是乳腺癌混合物图谱领域的领导者。

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.