title: Oesophageal squamous cell carcinoma in high-risk Chinese populations: Possible role for vascular epithelial growth factor A.
abstract: BACKGROUND
  Mechanisms involved in wound healing play some role in carcinogenesis in multiple organs, likely by creating a chronic inflammatory milieu. This study sought to assess the role of genetic markers in selected inflammation-related genes involved in wound healing (interleukin (IL)-1a, IL-1b, IL-1 Receptor type I (IL-1Ra), IL-1 Receptor type II (IL-1Rb), tumour necrosis factor (TNF)-α, tumour necrosis factor receptor superfamily member (TNFRSF)1A, nuclear factor kappa beta (NF-kB)1, NF-kB2, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, hypoxia induced factor (HIF)-1α, vascular endothelial growth factor (VEGF)A and P-53) in risk to oesophageal squamous cell carcinoma (OSCC).
  
  
  METHODS
  We genotyped 125 tag single nucleotide polymorphism (SNP)s in 410 cases and 377 age and sex matched disease-free individuals from Nutritional Intervention Trial (NIT) cohort, and 546 cases and 556 controls individually matched for age, sex and neighbourhood from Shanxi case-control study, both conducted in high-risk areas of north-central China (1985-2007). Cox proportional-hazard models and conditional logistic regression models were used for SNPs analyses for NIT and Shanxi, respectively. Fisher's inverse test statistics were used to obtain gene-level significance.
  
  
  RESULTS
  Multiple SNPs were significantly associated with OSCC in both studies, however, none retained their significance after a conservative Bonferroni adjustment. Empiric p-values for tag SNPs in VEGFA in NIT were highly concentrated in the lower tail of the distribution, suggesting this gene may be influencing risk. Permutation tests confirmed the significance of this pattern. At the gene level, VEGFA yielded an empiric significance (P=0.027) in NIT. We also observed some evidence for interaction between environmental factors and some VEGFA tag SNPs.
  
  
  CONCLUSIONS
  Our finding adds further evidence for a potential role for markers in the VEGFA gene in the development and progression of early precancerous lesions of oesophagus.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. Electronic address: agolozar@jhu.edu.
authors.forename: Asieh
authors.initials: A
authors.lastname: Golozar
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: Patti E
authors.initials: PE
authors.lastname: Gravitt
authors.affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: Ingo
authors.initials: I
authors.lastname: Ruczinski
authors.affiliation: Department of Epidemiology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
authors.forename: You-Lin
authors.initials: YL
authors.lastname: Qiao
authors.affiliation: Department of Epidemiology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
authors.forename: Jin-Hu
authors.initials: JH
authors.lastname: Fan
authors.affiliation: Shanxi Cancer Hospital, Taiyuan, Shanxi, People's Republic of China.
authors.forename: Ti
authors.initials: T
authors.lastname: Ding
authors.affiliation: Shanxi Cancer Hospital, Taiyuan, Shanxi, People's Republic of China.
authors.forename: Ze-Zhong
authors.initials: ZZ
authors.lastname: Tang
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Arash
authors.initials: A
authors.lastname: Etemadi
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Paula L
authors.initials: PL
authors.lastname: Hyland
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Lemin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Chaoyu
authors.initials: C
authors.lastname: Wang
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Sanford M
authors.initials: SM
authors.lastname: Dawsey
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Neal D
authors.initials: ND
authors.lastname: Freedman
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Christian C
authors.initials: CC
authors.lastname: Abnet
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Alisa M
authors.initials: AM
authors.lastname: Goldstein
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Taylor
mesh_terms: D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000453:epidemiology* / Q000378:metabolism*; D016022:Case-Control Studies; D002681:China; D015331:Cohort Studies; D004938:Esophageal Neoplasms / Q000453:epidemiology* / Q000378:metabolism*; D004947:Esophagus / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D007249:Inflammation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011786:Quality Control; D015203:Reproducibility of Results; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Genetic marker; Genetics; Inflammation; Inflammation-related events; Oesophageal squamous cell carcinoma; VEGFA; Vascular endothelial growth factor A; Wound-healing