|Grant Number:||5R01CA111922-05 Interpret this number|
|Primary Investigator:||Wu, Xifeng|
|Organization:||Ut Md Anderson Cancer Ctr|
|Project Title:||Genetic Instability & Risk for Esophageal Carcinoma|
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.
Genome-wide methylation analysis shows similar patterns in Barrett's esophagus and esophageal adenocarcinoma.
Authors: Xu E, Gu J, Hawk ET, Wang KK, Lai M, Huang M, Ajani J, Wu X
Source: Carcinogenesis, 2013 Dec;34(12), p. 2750-6.
EPub date: 2013 Aug 29.
Risk assessment of esophageal adenocarcinoma using ?-H2AX assay.
Authors: Xu E, Gong Y, Gu J, Jie L, Ajani JA, Wu X
Source: Cancer Epidemiol Biomarkers Prev, 2013 Oct;22(10), p. 1797-804.
EPub date: 2013 Jul 31.
Association of mitochondrial DNA copy number in peripheral blood leukocytes with risk of esophageal adenocarcinoma.
Authors: Xu E, Sun W, Gu J, Chow WH, Ajani JA, Wu X
Source: Carcinogenesis, 2013 Nov;34(11), p. 2521-4.
EPub date: 2013 Jun 26.
MicroRNA expression signatures during malignant progression from Barrett's esophagus to esophageal adenocarcinoma.
Authors: Wu X, Ajani JA, Gu J, Chang DW, Tan W, Hildebrandt MA, Huang M, Wang KK, Hawk E
Source: Cancer Prev Res (Phila), 2013 Mar;6(3), p. 196-205.
Genetic susceptibility to bladder cancer risk and outcome.
Authors: Gu J, Wu X
Source: Per Med, 2011 May;8(3), p. 365-374.
Susceptibility locus for lung cancer at 15q25.1 is not associated with risk of pancreatic cancer.
Authors: Chen J, Wu X, Pande M, Amos CI, Killary AM, Sen S, Frazier ML
Source: Pancreas, 2011 Aug;40(6), p. 872-5.
A genome-wide association study identifies a locus on chromosome 14q21 as a predictor of leukocyte telomere length and as a marker of susceptibility for bladder cancer.
Authors: Gu J, Chen M, Shete S, Amos CI, Kamat A, Ye Y, Lin J, Dinney CP, Wu X
Source: Cancer Prev Res (Phila), 2011 Apr;4(4), p. 514-21.
EPub date: 2011 Apr 2.
Genetic variations in the sonic hedgehog pathway affect clinical outcomes in non-muscle-invasive bladder cancer.
Authors: Chen M, Hildebrandt MA, Clague J, Kamat AM, Picornell A, Chang J, Zhang X, Izzo J, Yang H, Lin J, Gu J, Chanock S, Kogevinas M, Rothman N, Silverman DT, Garcia-Closas M, Grossman HB, Dinney CP, Malats N, Wu X
Source: Cancer Prev Res (Phila), 2010 Oct;3(10), p. 1235-45.
EPub date: 2010 Sep 21.
Genome-wide catalogue of chromosomal aberrations in barrett's esophagus and esophageal adenocarcinoma: a high-density single nucleotide polymorphism array analysis.
Authors: Gu J, Ajani JA, Hawk ET, Ye Y, Lee JH, Bhutani MS, Hofstetter WL, Swisher SG, Wang KK, Wu X
Source: Cancer Prev Res (Phila), 2010 Sep;3(9), p. 1176-86.
EPub date: 2010 Jul 22.
Prostate stem cell antigen: a Jekyll and Hyde molecule?
Authors: Saeki N, Gu J, Yoshida T, Wu X
Source: Clin Cancer Res, 2010 Jul 15;16(14), p. 3533-8.
EPub date: 2010 May 25.
PI3K/PTEN/AKT/mTOR pathway genetic variation predicts toxicity and distant progression in lung cancer patients receiving platinum-based chemotherapy.
Authors: Pu X, Hildebrandt MA, Lu C, Lin J, Stewart DJ, Ye Y, Gu J, Spitz MR, Wu X
Source: Lung Cancer, 2011 Jan;71(1), p. 82-8.
EPub date: 2010 May 5.
Gastric cancer--an enigmatic and heterogeneous disease.
Authors: Shah MA, Ajani JA
Source: JAMA, 2010 May 5;303(17), p. 1753-4.
Energy balance, the PI3K-AKT-mTOR pathway genes, and the risk of bladder cancer.
Authors: Lin J, Wang J, Greisinger AJ, Grossman HB, Forman MR, Dinney CP, Hawk ET, Wu X
Source: Cancer Prev Res (Phila), 2010 Apr;3(4), p. 505-17.
EPub date: 2010 Mar 30.
MicroRNA expression signatures in Barrett's esophagus and esophageal adenocarcinoma.
Authors: Yang H, Gu J, Wang KK, Zhang W, Xing J, Chen Z, Ajani JA, Wu X
Source: Clin Cancer Res, 2009 Sep 15;15(18), p. 5744-52.
EPub date: 2009 Sep 8.
Polymorphisms in DNA repair genes, smoking, and bladder cancer risk: findings from the international consortium of bladder cancer.
Authors: Stern MC, Lin J, Figueroa JD, Kelsey KT, Kiltie AE, Yuan JM, Matullo G, Fletcher T, Benhamou S, Taylor JA, Placidi D, Zhang ZF, Steineck G, Rothman N, Kogevinas M, Silverman D, Malats N, Chanock S, Wu X, Karagas MR, Andrew AS, Nelson HH, Bishop DT, Sak SC, Choudhury A, Barrett JH, Elliot F, Corral R, Joshi AD, Gago-Dominguez M, Cortessis VK, Xiang YB, Gao YT, Vineis P, Sacerdote C, Guarrera S, Polidoro S, Allione A, Gurzau E, Koppova K, Kumar R, Rudnai P, Porru S, Carta A, Campagna M, Arici C, Park SS, Garcia-Closas M, International Consortium of Bladder Cancer
Source: Cancer Res, 2009 Sep 1;69(17), p. 6857-64.
EPub date: 2009 Aug 25.
Genome-wide profiling of chromosomal alterations in renal cell carcinoma using high-density single nucleotide polymorphism arrays.
Authors: Chen M, Ye Y, Yang H, Tamboli P, Matin S, Tannir NM, Wood CG, Gu J, Wu X
Source: Int J Cancer, 2009 Nov 15;125(10), p. 2342-8.
Constitutive short telomere length of chromosome 17p and 12q but not 11q and 2p is associated with an increased risk for esophageal cancer.
Authors: Xing J, Ajani JA, Chen M, Izzo J, Lin J, Chen Z, Gu J, Wu X
Source: Cancer Prev Res (Phila), 2009 May;2(5), p. 459-65.
EPub date: 2009 Apr 28.
Genetic susceptibility to esophageal cancer: the role of the nucleotide excision repair pathway.
Authors: Pan J, Lin J, Izzo JG, Liu Y, Xing J, Huang M, Ajani JA, Wu X
Source: Carcinogenesis, 2009 May;30(5), p. 785-92.
EPub date: 2009 Mar 6.
Family history and risk of renal cell carcinoma: results from a case-control study and systematic meta-analysis.
Authors: Clague J, Lin J, Cassidy A, Matin S, Tannir NM, Tamboli P, Wood CG, Wu X
Source: Cancer Epidemiol Biomarkers Prev, 2009 Mar;18(3), p. 801-7.
EPub date: 2009 Feb 24.
Cyclooxygenase-2 gene polymorphisms reduce the risk of oral premalignant lesions.
Authors: Pu X, Lippman SM, Yang H, Lee JJ, Wu X
Source: Cancer, 2009 Apr 1;115(7), p. 1498-506.
Genetic variations in the PI3K/PTEN/AKT/mTOR pathway are associated with clinical outcomes in esophageal cancer patients treated with chemoradiotherapy.
Authors: Hildebrandt MA, Yang H, Hung MC, Izzo JG, Huang M, Lin J, Ajani JA, Wu X
Source: J Clin Oncol, 2009 Feb 20;27(6), p. 857-71.
EPub date: 2009 Jan 21.
Genetic variations in microRNA-related genes are novel susceptibility loci for esophageal cancer risk.
Authors: Ye Y, Wang KK, Gu J, Yang H, Lin J, Ajani JA, Wu X
Source: Cancer Prev Res (Phila), 2008 Nov;1(6), p. 460-9.
Single nucleotide polymorphisms of microRNA machinery genes modify the risk of renal cell carcinoma.
Authors: Horikawa Y, Wood CG, Yang H, Zhao H, Ye Y, Gu J, Lin J, Habuchi T, Wu X
Source: Clin Cancer Res, 2008 Dec 1;14(23), p. 7956-62.
Germline genetic variations in drug action pathways predict clinical outcomes in advanced lung cancer treated with platinum-based chemotherapy.
Authors: Wu X, Lu C, Ye Y, Chang J, Yang H, Lin J, Gu J, Hong WK, Stewart D, Spitz MR
Source: Pharmacogenet Genomics, 2008 Nov;18(11), p. 955-65.
Genetic susceptibility to renal cell carcinoma: the role of DNA double-strand break repair pathway.
Authors: Margulis V, Lin J, Yang H, Wang W, Wood CG, Wu X
Source: Cancer Epidemiol Biomarkers Prev, 2008 Sep;17(9), p. 2366-73.
Genetic polymorphisms in double-strand break DNA repair genes associated with risk of oral premalignant lesions.
Authors: Yang H, Lippman SM, Huang M, Jack Lee J, Wang W, Spitz MR, Wu X
Source: Eur J Cancer, 2008 Jul;44(11), p. 1603-11.
EPub date: 2008 Jun 23.