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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA111922-05
Application #
8212588
Study Section
Special Emphasis Panel (ZRG1-HOP-N (03))
Program Officer
Zanetti, Krista A
Project Start
2008-03-10
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
5
Fiscal Year
2012
Total Cost
$503,936
Indirect Cost
$176,705
Name
University of Texas MD Anderson Cancer Center
Department
None
Type
Schools of Medicine
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Liang, Su; Sanchez-Espiridion, Beatriz; Xie, Huan et al. (2015) Determination of proline in human serum by a robust LC-MS/MS method: application to identification of human metabolites as candidate biomarkers for esophageal cancer early detection and risk stratification. Biomed Chromatogr 29:570-7
Xu, Enping; Gong, Yilei; Gu, Jian et al. (2013) Risk assessment of esophageal adenocarcinoma using ýý-H2AX assay. Cancer Epidemiol Biomarkers Prev 22:1797-804
Xu, Enping; Sun, Wenjie; Gu, Jian et al. (2013) Association of mitochondrial DNA copy number in peripheral blood leukocytes with risk of esophageal adenocarcinoma. Carcinogenesis 34:2521-4
Wu, Xifeng; Ajani, Jaffer A; Gu, Jian et al. (2013) MicroRNA expression signatures during malignant progression from Barrett's esophagus to esophageal adenocarcinoma. Cancer Prev Res (Phila) 6:196-205
Pu, Xia; Hildebrandt, Michelle A T; Lu, Charles et al. (2011) PI3K/PTEN/AKT/mTOR pathway genetic variation predicts toxicity and distant progression in lung cancer patients receiving platinum-based chemotherapy. Lung Cancer 71:82-8
Gu, Jian; Wu, Xifeng (2011) Genetic susceptibility to bladder cancer risk and outcome. Per Med 8:365-374
Chen, Jinyun; Wu, Xifeng; Pande, Mala et al. (2011) Susceptibility locus for lung cancer at 15q25.1 is not associated with risk of pancreatic cancer. Pancreas 40:872-5
Shah, Manish A; Ajani, Jaffer A (2010) Gastric cancer--an enigmatic and heterogeneous disease. JAMA 303:1753-4
Gu, Jian; Ajani, Jaffer A; Hawk, Ernest T et al. (2010) Genome-wide catalogue of chromosomal aberrations in barrett's esophagus and esophageal adenocarcinoma: a high-density single nucleotide polymorphism array analysis. Cancer Prev Res (Phila) 3:1176-86
Stern, Mariana C; Lin, Jie; Figueroa, Jonine D et al. (2009) Polymorphisms in DNA repair genes, smoking, and bladder cancer risk: findings from the international consortium of bladder cancer. Cancer Res 69:6857-64

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