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Genetic Polymorphisms in DNA Repair Genes XRCC4 and XRCC5 and Aflatoxin B1–related Hepatocellular Carcinoma

Long, Xi-Daia,b; Zhao, Donga; Wang, Chaob; Huang, Xiao-Yingb; Yao, Jin-Guangb; Ma, Yunc; Wei, Zhong-Huad; Liu, Mind; Zeng, Li-Xiaoc; Mo, Xiao-Qiangb; Zhang, Jian-Juna; Xue, Fenga; Zhai, Boa; Xia, Qianga

doi: 10.1097/EDE.0b013e31829d2744

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.

Conclusion: XRCC4P may be a genetic modifier for the risk and outcome of hepatocellular carcinoma induced by AFB1 exposure.

From the aDepartment of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R.China; bDepartment of Pathology, Youjiang Medical College for Nationalities, Baise, P.R.China;cDepartment of Pathology, Guangxi Medical University, Nanning, P.R.China; and dDepartment of Pathology, the 6th People’s Hospital of Shanghai, Shanghai, China.

X.-D.L., D.Z., and C.W. contributed equally to this work.

This study was supported in part by the National Natural Science Foundation of China (No. 81160255), Innovation Program of Shanghai Municipal Education Commission (No. 13YZ035), the Natural Science Foundation of Guangxi (No. 2013GXNSFAA019251), and the Science Foundation of Youjiang Medical College for Nationalities (No. 2005 and 2008). The authors declare no competing financial interests.

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Correspondence: Xi-Dai Long or Qiang Xia, Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University Dongfang Road, NO. 1630, Shanghai 200127, China. E-mail: or

Received March 7, 2012

Accepted May 19, 2013

© 2013 by Lippincott Williams & Wilkins, Inc