Inherited genetic factors in breast cancer predisposition and tumor presentation

乳腺癌易感性和肿瘤表现的遗传因素

• 批准号: 8899478
• 负责人: Julie Dutil
• 金额: $ 33.77万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8899478
• 关键词: Admixture; Affect; African; Age; Alleles; Behavior; Bioinformatics; Biological Markers; Breast; Breast Cancer Genetics; Breast Cancer Patient; Breast Cancer Prevention; California; Cancer Center; Cancer Prognosis; Candidate Disease Gene; Characteristics; Clinical Management; Copy Number Polymorphism; DNA; DNA Repair; Data; Development; Disease; Early Diagnosis; Epidemiologic Studies; Epidemiologist; Equilibrium; Estrogens; European; Event; Family; Frequencies; Funding; Gene Dosage; Gene Expression; Gene Expression Profile; Gene Structure; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genetic study; Genomic Segment; Genomics; Genotype; Geographic Locations; Goals; Health; Hereditary Breast Carcinoma; Hispanics; Hormonal; Hormones; Incidence; Individual; Inherited; Intervention; Knowledge; Lead; Life; Life Style; Linkage Disequilibrium; Magnetic Resonance Imaging; Malignant neoplasm of lung; Malignant neoplasm of ovary; Mammary Neoplasms; Mammography; Manuscripts; Maps; Measures; Messenger RNA; Methods; Minority; Molecular Genetics; Mutation Spectra; Nucleotide Excision Repair; Participant; Pathology; Pathway interactions; Physicians; Piedra; Population; Population Study; Predisposition; Preparation; Prevention strategy; Progesterone; Public Health; Publishing; Puerto Rican; Puerto Rico; RNA; RNA Sequences; RNA Splicing; Recording of previous events; Research; Research Infrastructure; Research Personnel; Risk; Risk Factors; Risk Reduction; Role; San Francisco; Socioeconomic Status; Subgroup; Training; Transcript; Variant; Visit; Woman; Work; base; cancer genetics; cancer risk; career; case control; comparative; gene function; genetic variant; high risk; improved; innovation; interest; malignant breast neoplasm; medical schools; mortality; multidisciplinary; next generation sequencing; receptor; repaired; reproductive; screening; transcriptome sequencing; tumor

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.

描述（由申请人提供）：乳腺癌是高发病率和死亡率高的主要公共卫生问题。遗传因素已显示出影响对乳腺癌和预后的易感性。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遗传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。与非癌症对照相比，在波多黎各的乳腺癌病例中，DNA修复能力（DRC）水平的显着降低（DRC）水平大多是NER的活性。在特定的目标＃1中，我们将确定与乳腺癌风险相关的NER基因区域中的拷贝数变异。我们将首先使用靶向阵列比较杂交（CGH）筛选存在CNV的NER途径基因。接下来，我们将评估乳腺癌对照人群中确定的CNV的关联。在特定的目标＃2中，我们建议确定NER途径CNVS在定性（基因结构）或定量（基因表达水平）上的功能意义。我们将对鉴定CNV的NER基因途径基因进行靶向RNA-Sequencing（RNA-SEQ）。我们将搜索CNV相关的基因表达变化，剪接变体和融合转录本。特定目的＃3取决于我们的初步数据，表明在波多黎各妇女中，非洲血统与ER-PR-肿瘤风险更高有关。在此目标中，我们将使用混合链接不平衡的映射不平衡地鉴定乳腺癌患者中激素受体阴性肿瘤易感性的基因组区域。该方法利用了种群之间遗传变异频率的差异，以发现引起疾病的基因。该应用提出了一种综合而创新的策略，以提高我们对遗传学在乳腺癌中的作用的理解，并且它针对的是西班牙裔人群，这在遗传研究中通常不足。随着发现常见遗传变异的发现，这些变异可能会累积地识别风险分布的极端，人们可以通过平衡风险水平与适当的风险降低干预措施来设想“个性化预防”乳腺癌的“个性化预防”。拟议的研究的结果可以为这一目标做出重要贡献。拟议的项目有望通过为准备高质量手稿的基础提供基础，从而对PI的职业产生积极影响，这将导致R型资金。 Dutil博士在分子遗传学方面接受了良好的培训，我被一个强大的多学科团队包围：Matta博士是DNA维修方面的专家，将为1,084多名参与者提供研究人群； Massey博士是应用于基因组数据的生物信息学专家； Schabath博士是一位癌症遗传流行病学家； Ziv博士是乳腺癌混合映射领域的领导者。