Genetic Instability & Risk for Esophageal Carcinoma

遗传不稳定性

• 批准号: 7584203
• 负责人: Xifeng Wu
• 金额: $ 58.86万
• 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/7584203
• 关键词: 17p; 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 therapy; Recruitment Activity; Research Infrastructure; Research Personnel; Residencies; Risk; Risk Assessment; Risk Marker; Role; Screening procedure; Series; Single Nucleotide Polymorphism; Smoke; Smoking History; Subgroup; Surrogate Markers; Survival Rate; System; Telomere Length Maintenance; Telomere Maintenance Gene; Telomere Shortening; Texas; Time; Tissues; Tumor Tissue; United States; University of Texas M D Anderson Cancer Center; 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. PUBLIC HEALTH RELEVANCE: Esophageal cancer (EC) is the seventh leading cause of death from cancer among American men, and more than 90% of patients diagnosed with esophageal cancer will ultimately die of their disease. The vast majority of ECs are either esophageal squamous-cell carcinomas (ESCC) or esophageal adenocarcinoma (EAC). Once a rare tumor representing <10% of ECs in U.S., EAC is currently the cancer with the fastest increasing incidence in this country. In the past few decades, the incidence of EAC has increased by approximately 6-fold and replaced ESCC as the most common histological type in this country since the mid 1990s, whereas ESCC still predominates in eastern countries. The reason for this dramatic increase of EAC in western countries is unknown. In this application, we will recruit 600 EAC patients and 600 controls. We will collect comprehensive epidemiologic profiles and perform a series of genetic and biochemical assays. We will assess the associations between a variety of epidemiologic factors, such smoking history, alcohol consumption, dietary intake, obesity, physical activity, cancer family history, occupational exposures, previous medical history, etc., with the risk of EAC. We will also assess biomarkers that may predict the development of EAC. The long-term goal of this project is to build up a comprehensive risk assessment model for EAC and shed light on the dramatic increase of EAC incidence. The ability to identify high-risk subgroups of individuals for EAC will provide immense public health benefit for those high-risk people who may be subjected to close surveillance and chemoprevention.

描述（由申请人提供）：本申请建立在食管癌（EC）基础设施的基础上，该基础设施是我们用机构资金创建的，用于探索遗传不稳定性的作用，使用一组标记，包括端粒功能障碍和DNA损伤/或修复，作为食管癌（EAC）风险的预测因子。此外，我们将进行基因型/表型相关性，并将替代标记物（外周血淋巴细胞（pbl））与靶组织（肿瘤）中的遗传改变相关联，以进一步扩大我们对EAC肿瘤发生的理解。我们将从md安德森癌症中心收集600名未接受化疗或放疗的EAC患者，这些患者都是德克萨斯州的居民。我们还将招募600名控制者，这些控制者来自德克萨斯州地区基于人口的随机数字拨号。对照将按性别、年龄（5岁）、种族和居住地与患者相匹配。通过个人访谈获得全面的流行病学概况，包括吸烟史、饮酒史、饮食摄入量、体重指数（BMI）、身体活动、癌症家族史、职业暴露、既往病史和处方药使用等。有三个目的：1)评估代孕组织（pbl）遗传不稳定性的标志物。1.1. 使用高通量实时定量方法测定所有病例和对照的pbl的总端粒长度。我们的假设是端粒较短的个体比端粒较长的个体患EAC的风险更大。此外，我们将使用改进的基于实时荧光定量PCR的单端粒长度分析（STELA）方法，在所有病例和对照组的pbl中测定染色体特异性端粒长度（17p、2p和XpYp）。我们的假设是染色体17p端粒缩短与EAC风险增加特别相关。1.2. 估计端粒长度维持通路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风险增加有关。1.3. 定量苯并[a]芘二醇环氧化物（BPDE）}诱导（反映初始DNA损伤和核苷酸切除修复[NER]能力的净结果）和？-辐射诱导的pbl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），由Komet 4.0图像系统测量。我们的假设是，与对照组相比，病例表现出更高水平的诱导基因损伤。1.4. 估计DNA修复基因中涉及NER、BER和DSB通路的snp频率。我们的假设是NER、BER和DBS通路的不良基因型与EAC的风险增加有关。2)评估易感标志物的基因型-表型关联。2.1将pbl端粒长度与端粒维持途径基因snp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可以预测端粒功能障碍。2.2. 比较诱变剂引起的DNA损伤，通过彗星试验测量，与DNA修复基因中snp的频率。我们的假设是，NER通路的不良基因型将预测更高水平的bdpe诱导的DNA损伤，而BER和DSB通路的不良基因型将预测更高水平的？-辐射}引起的DNA损伤。3)代孕体（pbl）和靶组织中的相关标记物。我们将使用Illumina的Human CNV370 SNP阵列，在200个EAC的邻近正常组织和肿瘤组织中测定染色体畸变，这构成了遗传不稳定性的指标。我们的假设是，具有短端粒、不良基因型和/或高水平诱变原诱导的DNA损伤的个体在靶组织中发生染色体畸变的风险更高。我们将综合综合流行病学数据和上述研究的遗传数据，以评估EAC的风险。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。公共卫生相关性：食管癌（EC）是美国男性癌症死亡的第七大原因，超过90%的食管癌患者最终将死于他们的疾病。绝大多数ECs是食管鳞状细胞癌（ESCC）或食管腺癌（EAC）。在美国，EAC曾经是一种罕见的肿瘤，占ECs的比例<10%，目前是美国发病率增长最快的癌症。在过去的几十年里，EAC的发病率增加了大约6倍，自20世纪90年代中期以来，EAC取代ESCC成为该国最常见的组织学类型，而ESCC在东部国家仍占主导地位。西方国家EAC急剧增加的原因尚不清楚。在这个应用中，我们将招募600名EAC患者和600名对照组。我们将收集全面的流行病学资料，并进行一系列的遗传和生化分析。我们将评估各种流行病学因素，如吸烟史、饮酒、饮食摄入、肥胖、体育活动、癌症家族史、职业暴露、既往病史等与EAC风险之间的关系。我们还将评估可能预测EAC发展的生物标志物。该项目的长期目标是建立一个全面的EAC风险评估模型，并揭示EAC发病率急剧上升的原因。识别EAC高危亚群的能力将为那些可能受到密切监测和化学预防的高危人群提供巨大的公共卫生益处。