Genetic Instability & Risk for Esophageal Carcinoma

描述(申请人提供)：此应用程序建立在食道癌(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，以探索遗传不稳定的作用，使用一组标记物，包括端粒功能障碍和DNA损伤/或修复，作为食管腺癌(EAC)风险的预测指标。此外，我们将进行基因/表型关联，并将替代标记(外周血淋巴细胞)与靶组织(肿瘤)的遗传变化相关联，以进一步扩大我们对EAC肿瘤发生的理解。我们将从M.D.安德森癌症中心接收600名未接受化疗或放射治疗的EAC患者，他们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。对照将根据性别、年龄(5岁)、种族和居住地与患者匹配。通过个人访谈获得吸烟史、饮酒史、膳食摄入量、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全面的流行病学资料。1.1.使用高通量定量实时方法确定所有病例和对照的PBL中的总端粒长度。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，我们将使用一种改进的基于实时聚合酶链式反应的单个端粒长度分析(STELA)方法来测定所有病例和对照的外周血淋巴细胞中的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风险的增加特别相关。1.2.估计端粒长度维持途径基因的单核苷酸多态(SNPs)频率。我们的假设是，端粒长度维持途径的不利基因型与EAC的风险增加相关。1.3.量化苯并[a]芘二醇环氧化物(BPDE)诱导的(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)，如Komet 4.0图像系统所测量的。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SNPs的频率。我们的假设是，NER、BER和DBS通路的不利基因型与EAC的风险增加相关。2)评估易感标记物的基因型-表型相关性。2.1比较外周血淋巴细胞端粒长度与端粒长度维持途径基因中SNPs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.比较彗星试验检测的诱变剂诱导的DNA损伤与DNA修复基因中SNPs的频率。我们的假设是，NER途径的不利基因型将预测BDPE诱导的更高水平的DNA损伤，而BER和DSB途径的不利基因型将预测更高水平的辐射诱导的DNA损伤。3)代用品(PBL)和靶组织中的相关标志物。我们将使用Illumina的Human CNV370 SNP阵列来确定200例EAC邻近正常组织和肿瘤组织中的染色体畸变率，这是遗传不稳定性的一个指标。我们的假设是，具有短端粒、不利的基因类型和/或高水平的诱变剂诱导的DNA损伤的个体在目标组织中发生染色体异常的风险更高。我们将综合流行病学数据和上述研究的遗传数据来评估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，如强化筛查和化学预防干预。

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.