Grant Details
Grant Number: |
1R01CA111922-01A2 Interpret this number |
Primary Investigator: |
Wu, Xifeng |
Organization: |
University Of Tx Md Anderson Can Ctr |
Project Title: |
Genetic Instability & Risk for Esophageal Carcinoma |
Fiscal Year: |
2008 |
Abstract
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.
Publications
Common, germline genetic variations in the novel tumor suppressor BAP1 and risk of developing different types of cancer.
Authors: Lin M.
, Zhang L.
, Hildebrandt M.A.T.
, Huang M.
, Wu X.
, Ye Y.
.
Source: Oncotarget, 2017-09-26 00:00:00.0; 8(43), p. 74936-74946.
EPub date: 2017-08-24 00:00:00.0.
PMID: 29088836
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LC-MS/MS determination of d-mannose in human serum as a potential cancer biomarker.
Authors: White L.
, Ma J.
, Liang S.
, Sanchez-Espiridion B.
, Liang D.
.
Source: Journal Of Pharmaceutical And Biomedical Analysis, 2017-04-15 00:00:00.0; 137, p. 54-59.
EPub date: 2016-12-28 00:00:00.0.
PMID: 28092855
Related Citations
Identification Of Serum Markers Of Esophageal Adenocarcinoma By Global And Targeted Metabolic Profiling
Authors: Sanchez-Espiridion B.
, Liang D.
, Ajani J.A.
, Liang S.
, Ye Y.
, Hildebrandt M.A.
, Gu J.
, Wu X.
.
Source: Clinical Gastroenterology And Hepatology : The Official Clinical Practice Journal Of The American Gastroenterological Association, 2015 Oct; 13(10), p. 1730-1737.e9.
PMID: 25998788
Related Citations
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
Authors: Liang S.
, Sanchez-Espiridion B.
, Xie H.
, Ma J.
, Wu X.
, Liang D.
.
Source: Biomedical Chromatography : Bmc, 2015 Apr; 29(4), p. 570-7.
PMID: 25164985
Related Citations
Genome-wide Methylation Analysis Shows Similar Patterns In Barrett's Esophagus And Esophageal Adenocarcinoma
Authors: Xu E.
, Gu J.
, Hawk E.T.
, Wang K.K.
, Lai M.
, Huang M.
, Ajani J.
, Wu X.
.
Source: Carcinogenesis, 2013 Dec; 34(12), p. 2750-6.
PMID: 23996928
Related Citations
Association Of Mitochondrial Dna Copy Number In Peripheral Blood Leukocytes With Risk Of Esophageal Adenocarcinoma
Authors: Xu E.
, Sun W.
, Gu J.
, Chow W.H.
, Ajani J.A.
, Wu X.
.
Source: Carcinogenesis, 2013 Nov; 34(11), p. 2521-4.
PMID: 23803692
Related Citations
Risk Assessment Of Esophageal Adenocarcinoma Using ¿-h2ax Assay
Authors: Xu E.
, Gong Y.
, Gu J.
, Jie L.
, Ajani J.A.
, Wu X.
.
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2013 Oct; 22(10), p. 1797-804.
PMID: 23904462
Related Citations
Microrna Expression Signatures During Malignant Progression From Barrett's Esophagus To Esophageal Adenocarcinoma
Authors: Wu X.
, Ajani J.A.
, Gu J.
, Chang D.W.
, Tan W.
, Hildebrandt M.A.
, Huang M.
, Wang K.K.
, Hawk E.
.
Source: Cancer Prevention Research (philadelphia, Pa.), 2013 Mar; 6(3), p. 196-205.
PMID: 23466817
Related Citations
Barrett's Esophagus: A Review Of Biology And Therapeutic Approaches
Authors: Kountourakis,P.
, Ajani,J.A.
, Davila,M.
, Lee,J.H.
, Bhutani,M.S.
, Izzo,J.G.
.
Source: Gastrointestinal Cancer Research : Gcr, 2012 Mar; 5(2), p. 49-57.
PMID: 22690258
Related Citations
Susceptibility locus for lung cancer at 15q25.1 is not associated with risk of pancreatic cancer.
Authors: Chen J.
, Wu X.
, Pande M.
, Amos C.I.
, Killary A.M.
, Sen S.
, Frazier M.L.
.
Source: Pancreas, 2011 Aug; 40(6), p. 872-5.
PMID: 21697764
Related Citations
Genetic Susceptibility To Bladder Cancer Risk And Outcome
Authors: Gu J.
, Wu X.
.
Source: Personalized Medicine, 2011 May; 8(3), p. 365-374.
PMID: 21927616
Related Citations
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 C.I.
, Kamat A.
, Ye Y.
, Lin J.
, Dinney C.P.
, Wu X.
.
Source: Cancer Prevention Research (philadelphia, Pa.), 2011 Apr; 4(4), p. 514-21.
PMID: 21460395
Related Citations
Pi3k/pten/akt/mtor Pathway Genetic Variation Predicts Toxicity And Distant Progression In Lung Cancer Patients Receiving Platinum-based Chemotherapy
Authors: Pu,X.
, Hildebrandt,M.A.
, Lu,C.
, Lin,J.
, Stewart,D.J.
, Ye,Y.
, Gu,J.
, Spitz,M.R.
, Wu,X.
.
Source: Lung Cancer (amsterdam, Netherlands), 2011 Jan; 71(1), p. 82-8.
PMID: 20447721
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Genetic Variations In The Sonic Hedgehog Pathway Affect Clinical Outcomes In Non-muscle-invasive Bladder Cancer
Authors: Chen M.
, Hildebrandt M.A.
, Clague J.
, Kamat A.M.
, Picornell A.
, Chang J.
, Zhang X.
, Izzo J.
, Yang H.
, Lin J.
, et al.
.
Source: Cancer Prevention Research (philadelphia, Pa.), 2010 Oct; 3(10), p. 1235-45.
PMID: 20858759
Related Citations
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,J.A.
, Hawk,E.T.
, Ye,Y.
, Lee,J.H.
, Bhutani,M.S.
, Hofstetter,W.L.
, Swisher,S.G.
, Wang,K.K.
, Wu,X.
.
Source: Cancer Prevention Research (philadelphia, Pa.), 2010 Sep; 3(9), p. 1176-86.
PMID: 20651033
Related Citations
Prostate Stem Cell Antigen: A Jekyll And Hyde Molecule?
Authors: Saeki N.
, Gu J.
, Yoshida T.
, Wu X.
.
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2010-07-15 00:00:00.0; 16(14), p. 3533-8.
PMID: 20501618
Related Citations
Gastric Cancer--an Enigmatic And Heterogeneous Disease
Authors: Shah,M.A.
, Ajani,J.A.
.
Source: Jama : The Journal Of The American Medical Association, 2010-05-05 00:00:00.0; 303(17), p. 1753-4.
PMID: 20442394
Related Citations
Energy Balance, The Pi3k-akt-mtor Pathway Genes, And The Risk Of Bladder Cancer
Authors: Lin,J.
, Wang,J.
, Greisinger,A.J.
, Grossman,H.B.
, Forman,M.R.
, Dinney,C.P.
, Hawk,E.T.
, Wu,X.
.
Source: Cancer Prevention Research (philadelphia, Pa.), 2010 Apr; 3(4), p. 505-17.
PMID: 20354165
Related Citations
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,N.M.
, Wood,C.G.
, Gu,J.
, Wu,X.
.
Source: International Journal Of Cancer. Journal International Du Cancer, 2009-11-15 00:00:00.0; 125(10), p. 2342-8.
PMID: 19521957
Related Citations
Microrna Expression Signatures In Barrett's Esophagus And Esophageal Adenocarcinoma
Authors: Yang,H.
, Gu,J.
, Wang,K.K.
, Zhang,W.
, Xing,J.
, Chen,Z.
, Ajani,J.A.
, Wu,X.
.
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2009-09-15 00:00:00.0; 15(18), p. 5744-52.
PMID: 19737949
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Polymorphisms In Dna Repair Genes, Smoking, And Bladder Cancer Risk: Findings From The International Consortium Of Bladder Cancer
Authors: Stern M.C.
, Lin J.
, Figueroa J.D.
, Kelsey K.T.
, Kiltie A.E.
, Yuan J.M.
, Matullo G.
, Fletcher T.
, Benhamou S.
, Taylor J.A.
, et al.
.
Source: Cancer Research, 2009-09-01 00:00:00.0; 69(17), p. 6857-64.
PMID: 19706757
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Genetic Susceptibility To Esophageal Cancer: The Role Of The Nucleotide Excision Repair Pathway
Authors: Pan,J.
, Lin,J.
, Izzo,J.G.
, Liu,Y.
, Xing,J.
, Huang,M.
, Ajani,J.A.
, Wu,X.
.
Source: Carcinogenesis, 2009 May; 30(5), p. 785-92.
PMID: 19270000
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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,J.A.
, Chen,M.
, Izzo,J.
, Lin,J.
, Chen,Z.
, Gu,J.
, Wu,X.
.
Source: Cancer Prevention Research (philadelphia, Pa.), 2009 May; 2(5), p. 459-65.
PMID: 19401529
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Cyclooxygenase-2 Gene Polymorphisms Reduce The Risk Of Oral Premalignant Lesions
Authors: Pu,X.
, Lippman,S.M.
, Yang,H.
, Lee,J.J.
, Wu,X.
.
Source: Cancer, 2009-04-01 00:00:00.0; 115(7), p. 1498-506.
PMID: 19197984
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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,N.M.
, Tamboli,P.
, Wood,C.G.
, Wu,X.
.
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2009 Mar; 18(3), p. 801-7.
PMID: 19240244
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Genetic Variations In The Pi3k/pten/akt/mtor Pathway Are Associated With Clinical Outcomes In Esophageal Cancer Patients Treated With Chemoradiotherapy
Authors: Hildebrandt,M.A.
, Yang,H.
, Hung,M.C.
, Izzo,J.G.
, Huang,M.
, Lin,J.
, Ajani,J.A.
, Wu,X.
.
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2009-02-20 00:00:00.0; 27(6), p. 857-71.
PMID: 19164214
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Single Nucleotide Polymorphisms Of Microrna Machinery Genes Modify The Risk Of Renal Cell Carcinoma
Authors: Horikawa,Y.
, Wood,C.G.
, Yang,H.
, Zhao,H.
, Ye,Y.
, Gu,J.
, Lin,J.
, Habuchi,T.
, Wu,X.
.
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2008-12-01 00:00:00.0; 14(23), p. 7956-62.
PMID: 19047128
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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,W.K.
, Stewart,D.
, Spitz,M.R.
.
Source: Pharmacogenetics And Genomics, 2008 Nov; 18(11), p. 955-65.
PMID: 18854777
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Genetic Variations In Microrna-related Genes Are Novel Susceptibility Loci For Esophageal Cancer Risk
Authors: Ye,Y.
, Wang,K.K.
, Gu,J.
, Yang,H.
, Lin,J.
, Ajani,J.A.
, Wu,X.
.
Source: Cancer Prevention Research (philadelphia, Pa.), 2008 Nov; 1(6), p. 460-9.
PMID: 19138993
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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,C.G.
, Wu,X.
.
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2008 Sep; 17(9), p. 2366-73.
PMID: 18768505
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Genetic Polymorphisms In Double-strand Break Dna Repair Genes Associated With Risk Of Oral Premalignant Lesions
Authors: Yang,H.
, Lippman,S.M.
, Huang,M.
, Jack Lee,J.
, Wang,W.
, Spitz,M.R.
, Wu,X.
.
Source: European Journal Of Cancer (oxford, England : 1990), 2008 Jul; 44(11), p. 1603-11.
PMID: 18579371
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Bpde Induced Lymphocytic Chromosome 3p Deletions May Predict Renal Cell Carcinoma Risk
Authors: Zhu,Y.
, Horikawa,Y.
, Yang,H.
, Wood,C.G.
, Habuchi,T.
, Wu,X.
.
Source: The Journal Of Urology, 2008 Jun; 179(6), p. 2416-21.
PMID: 18433782
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Modulation Of Dna Damage/dna Repair Capacity By Xpc Polymorphisms
Authors: Zhu Y.
, Yang H.
, Chen Q.
, Lin J.
, Grossman H.B.
, Dinney C.P.
, Wu X.
, Gu J.
.
Source: Dna Repair, 2008-02-01 00:00:00.0; 7(2), p. 141-8.
PMID: 17923445
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Deficiency of cell cycle checkpoints and DNA repair system predispose individuals to esophageal cancer.
Authors: Shao L.
, Hittelman W.N.
, Lin J.
, Yang H.
, Ajani J.A.
, Wu X.
.
Source: Mutation Research, 2006-12-01 00:00:00.0; 602(1-2), p. 143-50.
EPub date: 2006-12-01 00:00:00.0.
PMID: 17011594
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Genetic Variations In Radiation And Chemotherapy Drug Action Pathways Predict Clinical Outcomes In Esophageal Cancer
Authors: Wu X.
, Gu J.
, Wu T.T.
, Swisher S.G.
, Liao Z.
, Correa A.M.
, Liu J.
, Etzel C.J.
, Amos C.I.
, Huang M.
, et al.
.
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2006-08-10 00:00:00.0; 24(23), p. 3789-98.
PMID: 16785472
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Predictors of esophageal cancer risk: assessment of susceptibility to DNA damage using comet assay.
Authors: Shao L.
, Lin J.
, Huang M.
, Ajani J.A.
, Wu X.
.
Source: Genes, Chromosomes & Cancer, 2005 Dec; 44(4), p. 415-22.
PMID: 16114035
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Pharmacogenetics In Esophageal Cancer
Authors: Wu,X.
, Lu,C.
, Chiang,S.S.
, Ajani,J.A.
.
Source: Seminars In Oncology, 2005 Dec; 32(6 Suppl 9), p. S87-9.
PMID: 16399440
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