Genetic Instability & Risk for Esophageal Carcinoma

描述（由申请人提供）：本申请建立在我们利用机构资金创建的食管癌 (EC) 基础设施的基础上，旨在使用一组标记物（包括端粒功能障碍和 DNA 损伤/或修复）作为食管腺癌 (EAC) 风险的预测因子来探索遗传不稳定性的作用。此外，我们将进行基因型/表型相关性并将替代标记（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。我们将从 M.D. 安德森癌症中心招募 600 名未接受化疗或放疗且为德克萨斯州居民的 EAC 患者。我们还将招募 600 名对照者，这些对照者是通过德克萨斯州地区基于人口的随机数字拨号确定的。对照组将按性别、年龄 (} 5 岁)、种族和居住地与患者进行匹配。通过个人访谈获得全面的流行病学概况，包括吸烟史、饮酒量、饮食摄入量、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。目标有三个：1）评估替代组织中遗传不稳定性的标志物（PBL）。 1.1.使用高通量定量实时方法确定所有情况和对照中 PBL 中的总体端粒长度。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，我们将使用基于改良实时 PCR 的单端粒长度分析 (STELA) 方法确定所有病例和对照中 PBL 中染色体特异性端粒长度（17p、2p 和 XpYp）。我们的假设是，17p 号染色体端粒缩短与 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利基因型与 EAC 风险增加相关。 1.3.量化 PBL 中苯并[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 β-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），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遗传损伤。 1.4.估计与 NER、BER 和 DSB 途径相关的 DNA 修复基因中 SNP 的频率。我们的假设是 NER、BER 和 DBS 通路的不利基因型与 EAC 风险增加相关。 2) 评估易感性标记的基因型-表型关联。 2.1 比较PBL中的端粒长度与端粒长度维持通路基因中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.将彗星试验测量的诱变剂诱导的 DNA 损伤与 DNA 修复基因中 SNP 的频率进行比较。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，而 BER 和 DSB 途径的不利基因型将预测更高水平的 β-辐射诱导的 DNA 损伤。 3) 关联替代物 (PBL) 和靶组织中的标记。我们将使用 Illumina 的人类 CNV370 SNP 阵列确定 200 个 EAC 的邻近正常组织和肿瘤组织中的染色体畸变，该畸变构成遗传不稳定的指标。我们的假设是，具有短端粒、不良基因型和/或高水平诱变剂诱导的 DNA 损伤的个体在目标组织中出现染色体畸变的风险较高。我们将综合流行病学数据与上述研究的遗传数据来评估 EAC 风险。使用微创手术（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措施。

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.