title: Genetic polymorphisms in DNA repair genes XRCC4 and XRCC5 and aflatoxin B1-related hepatocellular carcinoma.
abstract: BACKGROUND
  Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity and may play an important role in carcinogenesis. We investigated the role of genetic polymorphisms at XRCC4 codon 247 (rs3734091, XRCC4P) and XRCC5 codon 180 (rs80309960, XRCC5P) in liver cancer (hepatocellular carcinoma) caused by aflatoxin B1 (AFB1).
  
  
  METHODS
  A hospital-based case-control study, including 1499 liver cancer cases and 2045 controls without any liver disease, was conducted in a high aflatoxin exposure area in the Guangxi region of China to assess the relationship between these two polymorphisms and aflatoxin-related liver cancer risk and prognosis. Genotypes, mRNA levels, and the hot-spot mutation of TP53 gene (TP53M) related to AFB1 exposure was tested using TaqMan-PCR technique. XRCC4 protein level was analyzed by immunohistochemistry.
  
  
  RESULTS
  For XRCC4P and XRCC5P, only XRCC4P modified liver cancer risk. Compared with the homozygote of XRCC4 codon 247 Ala alleles (XRCC4-AA), the genotypes of XRCC4 codon 247 Ser alleles (namely XRCC4-AS or -SS) increased liver cancer risk (odds ratio [OR] = 1.35 and 2.02, respectively). Significant interactive effects between risk genotypes (OR > 1) and aflatoxin exposure status were also observed in the joint effects analysis. Moreover, this polymorphism was associated not only with lower XRCC4 expression levels but also with higher AFB1-DNA adduct levels and increasing TP53M and portal vein tumor risk. Additionally, XRCC4P modified the recurrence-free survival and overall survival of cases, especially under conditions of high aflatoxin exposure.
  
  
  CONCLUSIONS
  XRCC4P may be a genetic modifier for the risk and outcome of hepatocellular carcinoma induced by AFB1 exposure.
authors.affiliation: Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R.China. sjtulongxd@263.net
authors.forename: Xi-Dai
authors.initials: XD
authors.lastname: Long
authors.forename: Dong
authors.initials: D
authors.lastname: Zhao
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Huang
authors.forename: Jin-Guang
authors.initials: JG
authors.lastname: Yao
authors.forename: Yun
authors.initials: Y
authors.lastname: Ma
authors.forename: Zhong-Hua
authors.initials: ZH
authors.lastname: Wei
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Li-Xiao
authors.initials: LX
authors.lastname: Zeng
authors.forename: Xiao-Qiang
authors.initials: XQ
authors.lastname: Mo
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Xue
authors.forename: Bo
authors.initials: B
authors.lastname: Zhai
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
mesh_terms: D000328:Adult; D016604:Aflatoxin B1 / Q000633:toxicity*; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000235:genetics*; D016022:Case-Control Studies; D003062:Codon / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004781:Environmental Exposure / Q000706:statistics & numerical data; D005260:Female; D005500:Follow-Up Studies; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D000072200:Ku Autoantigen; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D018570:Risk Assessment; D013997:Time Factors
chemical_list: D003062:Codon; D004268:DNA-Binding Proteins; C101467:XRCC4 protein, human; D016604:Aflatoxin B1; D004265:DNA Helicases; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen