Genetic Instability & Risk for Esophageal Carcinoma

遗传不稳定性

• 批准号: 7766952
• 负责人: Xifeng Wu
• 金额: $ 59.89万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-10 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7766952
• 关键词: 17p; 5 year old; Age; Alcohol consumption; American; Area; Base Excision Repairs; Benzo(a)pyrene; Biochemical; Biological Assay; Biological Markers; Bladder; Blood specimen; Body mass index; Cancer Center; Cause of Death; Cessation of life; Chemoprevention; Chemopreventive Agent; Chromosomal Instability; Chromosome abnormality; Chromosomes; Clinical; Clinical Oncology; Comet Assay; Constitutional; Country; DNA Damage; DNA Repair; DNA Repair Gene; Data; Development; Diagnosis; Diet; Dietary intake; Digit structure; Disease; Doctor of Medicine; Double Strand Break Repair; Drug usage; Early Diagnosis; Epidemiologic Factors; Epidemiology; Epithelial; Epoxy Compounds; Esophageal; Esophageal Adenocarcinoma; Esophageal Squamous Cell Carcinoma; Esophageal carcinoma; Ethnic Origin; Etiology; Exhibits; Family Cancer History; Foundations; Frequencies; Functional disorder; Funding; Gender; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genomic Instability; Genotype; Glycols; Goals; Health Benefit; Human; Image; Incidence; Individual; Intervention; Interview; Investigation; Kidney; Knowledge; Length; Light; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of lung; Measures; Medical History; Methods; Modeling; Molecular; Molecular Biology; Mutagens; Mutation; Natural History; Normal tissue morphology; Nucleotide Excision Repair; Obesity; Occupational Exposure; Pathway interactions; Patients; Peripheral Blood Lymphocyte; Phenotype; Physical activity; Population; Positioning Attribute; Predisposition; Procedures; Public Health; Radiation; Radiation Induced DNA Damage; Radiation therapy; Recruitment Activity; Research Infrastructure; Research Personnel; Residencies; Risk; Risk Assessment; Risk Marker; Role; Screening procedure; Series; Single Nucleotide Polymorphism; Smoking; Smoking History; Subgroup; Surrogate Markers; Survival Rate; System; Telomere Length Maintenance; Telomere Maintenance Gene; Telomere Shortening; Texas; Time; Tissues; Tumor Tissue; United States; Virulent; base; carcinogenesis; case control; chemotherapy; density; epidemiologic data; gene repair; high risk; indexing; men; minimally invasive; multidisciplinary; outcome forecast; population based; public health relevance; repaired; sex; telomere; tumor; tumorigenesis

DESCRIPTION (provided by applicant): This application builds on the esophageal cancer (EC) infrastructure that we have created with institutional funds to explore the role of genetic instability using a panel of markers including telomere dysfunction and DNA damage/or repair as predictors of esophageal adenocarcinoma (EAC) risk. In addition, we will perform genotypic/phenotypic correlations and correlate surrogate markers (peripheral blood lymphocytes (PBLs)) with genetic alterations in target tissue (tumor) to further expand our understanding of EAC tumorigenesis. We will accrue 600 patients with EAC from M.D. Anderson Cancer Center who have not received chemotherapy or radiotherapy and are residents of Texas. We will also recruit 600 controls identified from population-based random digit dialing in the Texas area. The controls will be matched to the patients by sex, age (} 5 years), ethnicity, and residency. Comprehensive epidemiologic profiles will be obtained by personal interview on smoking history, alcohol consumption, dietary intake, body mass index (BMI), physical activity, cancer family history, occupational exposures, previous medical history, and prescription drug use, etc. There are three Aims: 1) Assess markers of genetic instability in surrogate tissue (PBLs). 1.1. Determine overall telomere length in PBLs in all cases and controls using a high-throughput quantitative real-time method. Our hypothesis is that individuals with shortened telomeres are at greater risk for EAC than those with long telomeres. In addition, we will determine chromosome specific telomere length (17p, 2p, and XpYp) in PBLs in all cases and controls using a modified real-time PCR based single telomere length analysis (STELA) method. Our hypothesis is that chromosome 17p telomere shortening is specifically associated with increased risk for EAC. 1.2. Estimate the frequencies of single-nucleotide polymorphisms (SNPs) in genes in telomere length maintenance pathway. Our hypothesis is that adverse genotypes of the telomere length maintenance pathway are associated with an increased risk for EAC. 1.3. Quantify benzo[a]pyrene diol-epoxide (BPDE)}induced (reflecting net results of initial DNA damage and nucleotide excision repair [NER] capacity) and ?-radiation- induced genetic damage (reflecting net results of initial DNA damage and base excision repair [BER] as well as double-stranded-break repair [DSB] capacities) in PBLs, as measured by the Komet 4.0 image system. Our hypothesis is that cases exhibit higher levels of induced genetic damage compared with controls. 1.4. Estimate the frequencies of SNPs in DNA repair genes implicated in the NER, BER, and the DSB pathways. Our hypothesis is that adverse genotypes of the NER, BER, and DBS pathways are associated with an increased risk for EAC. 2) Assess genotype-phenotype associations for markers of susceptibility. 2.1 Compare telomere length in PBLs with the frequencies of SNPs in genes in telomere length maintenance pathway. Our hypothesis is that the adverse genotypes of telomere length maintenance pathway will predict telomere dysfunction. 2.2. Compare mutagen-induced DNA damage as measured by the comet assay, with the frequencies of SNPs in DNA repair genes. Our hypothesis is that the adverse genotypes of the NER pathway will predict higher levels of BDPE-induced DNA damage and that the adverse genotypes of the BER and DSB pathways will predict higher levels of ?-radiation}induced DNA damage. 3) Correlate markers in surrogate (PBLs) and target tissue. We will determine chromosomal aberrations, which constitute an index of genetic instability, in adjacent normal tissue and tumor tissue of 200 EAC using Illumina's Human CNV370 SNP array. Our hypothesis is that individuals with short telomeres, adverse genotypes, and/or high levels of mutagen- induced DNA damage are at a higher risk for chromosomal aberrations in the target tissue. We will integrate comprehensive epidemiologic data with the genetic data from the studies described above to assess EAC risk. The ability to rapidly screen individuals for risk, using minimally invasive procedures (blood samples), has immense clinical implication, such as intensive screening and chemopreventive interventions.

描述（由申请人提供）：此申请基于我们使用机构资金创建的食道癌（EC）基础设施，以探索使用一组标记物的遗传不稳定性的作用腺癌（EAC）风险。此外，我们将执行基因型/表型相关性，并将替代标记物（外周血淋巴细胞（PBLS））与靶组织（肿瘤）的遗传改变相关联，以进一步扩展我们对EAC肿瘤发生的理解。我们将吸引600名来自M.D. Anderson癌症中心的EAC患者，他们尚未接受化疗或放疗，并且是德克萨斯州的居民。我们还将从德克萨斯地区的基于人群的随机数字拨号中招募600个对照。对照组将按性别，年龄（} 5岁），种族和居住权与患者匹配。全面的流行病学概况将通过有关吸烟史，饮酒，饮食摄入量，体重指数（BMI），体育锻炼，癌症家族史，职业暴露，以前的病史和处方药的个人访谈来获得。目的：1）评估替代组织（PBL）中遗传不稳定性的标志物。 1.1。在所有情况下，使用高通量定量实时方法确定PBL的总体端粒长度。我们的假设是，端粒缩短的个体对EAC的风险比长端粒的人更大。此外，在所有情况下，我们将在PBL中确定PBL中的染色体特异性端粒长度（17p，2p和XPYP），并使用基于基于的实时PCR的单端粒长度分析（Stela）方法进行对照。我们的假设是，17p型端粒缩短染色体与EAC风险增加特别有关。 1.2。估计端粒长度维持途径中基因中单核苷酸多态性（SNP）的频率。我们的假设是，端粒长度维持途径的不良基因型与EAC风险增加有关。 1.3。量化苯并[a] pyrene二醇 - 环氧化物（BPDE）}诱导（反映了初始DNA损伤和核苷酸切除修复的净结果[NER]容量）和？定性诱导的遗传损害（反映了初始DNA损伤的净结果，通过KOMET 4.0图像系统测量，PBL的维修[BER]以及双链破裂维修[DSB]容量）。我们的假设是，与对照组相比，病例表现出更高水平的遗传损害。 1.4。估计与NER，BER和DSB途径有关的DNA修复基因中SNP的频率。我们的假设是，NER，BER和DBS途径的不良基因型与EAC风险增加有关。 2）评估易感性标记的基因型 - 表型关联。 2.1将PBL中的端粒长度与端粒长度维护途径中基因中SNP的频率进行比较。我们的假设是，端粒长度维持途径的不良基因型将预测端粒功能障碍。 2.2。比较彗星测定法测量的诱变诱导的DNA损伤与DNA修复基因中SNP的频率。我们的假设是，NER途径的不良基因型将预测较高水平的BDPE诱导的DNA损伤，并且BER和DSB途径的不良基因型将预测较高的水平？放射}诱导的DNA损伤。 3）将替代物（PBL）和靶组织中的标记相关。我们将使用Illumina的人类CNV370 SNP阵列来确定在200 EAC的相邻正常组织和200 EAC的肿瘤组织中构成遗传不稳定性指数的染色体畸变。我们的假设是，端粒短，不良基因型和/或高水平的诱变DNA损伤的个体面临靶组织中染色体畸变的风险更高。我们将将全面的流行病学数据与上述研究的遗传数据相结合，以评估EAC风险。使用最小的侵入性程序（血液样本）快速筛选个人冒险的能力具有巨大的临床意义，例如强化筛查和化学预防干预措施。