Genetic Instability & Risk for Esophageal Carcinoma

遗传不稳定性

• 批准号: 8015279
• 负责人: Xifeng Wu
• 金额: $ 57.95万
• 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/8015279
• 关键词: 17p; 5 year old; Age; Alcohol consumption; American; Area; Base Excision Repairs; Benzo(a)pyrene; Bladder; Blood specimen; Body mass index; Cancer Center; Cause of Death; Cessation of life; Chemopreventive Agent; Chromosomal Instability; Chromosome abnormality; Chromosomes; Clinical; Clinical Oncology; Comet Assay; Constitutional; Country; DNA Damage; DNA Repair; DNA Repair Gene; Data; Diagnosis; Diet; Dietary intake; Digit structure; Disease; Doctor of Medicine; Double Strand Break Repair; Drug usage; Early Diagnosis; 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; Human; Image; Incidence; Individual; Intervention; Interview; Investigation; Kidney; Knowledge; Length; 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; Radiation; Radiation Induced DNA Damage; Radiation therapy; Recruitment Activity; Research Infrastructure; Research Personnel; Residencies; Risk; Risk Marker; Role; Screening procedure; Single Nucleotide Polymorphism; Smoking; Smoking History; 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; 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）：本申请建立在我们使用机构基金创建的食管癌（EC）基础设施的基础上，使用一组标记物（包括端粒功能障碍和DNA损伤/或修复）探索遗传不稳定性的作用，作为食管腺癌（EAC）风险的预测因子。此外，我们将进行基因型/表型相关性研究，并将替代标志物（外周血淋巴细胞（PBL））与靶组织（肿瘤）的遗传改变相关联，以进一步扩大我们对EAC肿瘤发生的理解。我们将招募600名来自M.D.的EAC患者。安德森癌症中心谁没有接受化疗或放疗，是得克萨斯州的居民。我们还将招募600名对照，这些对照是从德克萨斯州地区基于人口的随机数字拨号中确定的。对照组将按性别、年龄（> 5岁）、种族和居住地与患者匹配。通过个人访谈获得全面的流行病学资料，包括吸烟史、饮酒史、饮食摄入、体重指数（BMI）、体力活动、癌症家族史、职业暴露、既往病史和处方药使用等。目的有三：1）评估替代组织（PBL）中的遗传不稳定性标志物。1.1.使用高通量定量实时方法测定所有病例和对照中PBL的总体端粒长度。我们的假设是，端粒缩短的个体比端粒长的个体患EAC的风险更大。此外，我们将确定染色体特异性端粒长度（17 p，2 p，和XpYp）在PBL的所有情况下和控制使用改进的实时PCR为基础的单端粒长度分析（STELA）的方法。我们的假设是染色体17 p端粒缩短与EAC风险增加特别相关。1.2.估计端粒长度维持途径中基因的单核苷酸多态性（SNP）频率。我们的假设是端粒长度维持途径的不良基因型与EAC风险增加相关。1.3.定量诱导的苯并[a]芘二醇-环氧化物（BPDE）（反映初始DNA损伤和核苷酸切除修复[NER]能力的净结果）和？通过Komet 4.0图像系统测量PBL中辐射诱导的遗传损伤（反映初始DNA损伤和碱基切除修复[BER]以及双链断裂修复[DSB]能力的净结果）。我们的假设是，与对照组相比，病例表现出更高水平的诱导遗传损伤。1.4.估计与NER、BER和DSB通路有关的DNA修复基因中SNP的频率。我们的假设是NER、BER和DBS通路的不良基因型与EAC风险增加相关。2)评估易感性标志物的基因型-表型相关性。2.1比较外周血淋巴细胞中端粒长度与端粒长度维持途径基因中SNP的频率。我们的假设是端粒长度维持途径的不利基因型将预测端粒功能障碍。2.2.比较彗星试验测量的诱变剂诱导的DNA损伤与DNA修复基因中SNP的频率。我们的假设是，NER途径的不利基因型将预测更高水平的BDPE诱导的DNA损伤，BER和DSB途径的不利基因型将预测更高水平的？辐射引起的DNA损伤。3)将替代物（PBL）和靶组织中的标志物相关联。我们将使用Illumina的人类CNV 370 SNP阵列在200例EAC的相邻正常组织和肿瘤组织中确定染色体畸变，其构成遗传不稳定性的指标。我们的假设是，端粒短、基因型不良和/或诱变剂诱导的DNA损伤水平高的个体在靶组织中发生染色体畸变的风险较高。我们将综合综合流行病学数据和上述研究的遗传学数据，以评估EAC风险。使用微创程序（血液样本）快速筛查个体风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。