Quantitative assessment of mutations in hepatitis B virus genome with liver cirrhosis and hepatocellular carcinoma development

// Lei Yu 1, 2, * , Bao-fang Zhang 3, * , Ming-liang Cheng 2 , Xue-ke Zhao 2 , Quan Zhang 2 , Ya-xin Hu 2 , Hua-juan Liu 2 , Mao Mu 2 , Bi Wang 2, 4 , Guo-zhen Yang 2 , Li-li Zhu 2 , Shuai Zhang 5 , Yu-mei Yao 2 , Yi-ju Cheng 2 , Wang-sheng Li 6 1 The First Affiliated Hospital of Jinan University, Guangdong 510632, Guangzhou, China 2 The Affiliated Hospital, Guizhou Medical University, Guiyang 550004, Guizhou, China 3 The First Affiliated Hospital, Soochow University, Suzhou 215006, Jiangsu, China 4 Department of Eugenics and Genetics, Guiyang Maternal and Child Health-Care Hospital, Guiyang 550003, Guizhou, China 5 Department of Interventional Radiology, Cancer Hospital of Guizhou Medical University, Guiyang 550004, Guizhou, China 6 Department of Clinical Laboratory, Liupanshui People’s Hospital, Liupanshui 553401, Guizhou, China * These authors contributed equally to this work and should be considered as co-first authors Correspondence to: Ming-liang Cheng, e-mail: gmcmingliang_cheng@163.com Guo-zhen Yang, e-mail: gmcguozhen_yang@163.com Keywords: hepatitis B virus, hepatocellular carcinoma, liver cirrhosis, mutation, risk Received: February 29, 2016 Accepted: April 28, 2016 Published: May 17, 2016 ABSTRACT The long-term outcomes of liver cirrhosis (LC) and hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection are associated with specific HBV genotypes and mutations in the virus genome. However, a number of gene-disease association studies have yielded inconsistent results in the field. To investigate this inconsistency, we conducted a meta-analysis from 118 studies involving a total of 9,418 HCC cases, 2,697 LC cases, and 18,785 HBV-infected participants for 11 mutations of HBV to evaluate the epidemiological evidence of the relationship. Overall, 10 mutants (Pre-S mutation, A1762T/G1764A double mutations, G1896A, G1899A, T1753V, C1653T, G1766A, A1762T, G1764A, T1768A) were significantly associated with increased HCC risk with odds ratio (OR) range from 1.80 to 4.27, while no associations were found for C1858T. We found a significant dose–risk relationship between the number of mutations in HBV genome and HCC, in which high risks for HCC were associated with mutation numbers more than 5 (OR = 18.45, 95% CI: 7.86–43.29). By pooling 15 prospective studies, A1762T/G1764A, Pre-S, T1753V, and C1653T mutation was identified as good predictor of HCC risk, showing ORs from 1.73 to 4.54. In addition, significantly elevated LC risks were associated with 6 mutants (A1762T/G1764A double mutations, G1896A, G1899A, T1753V, C1653T, Pre-S mutation), with OR range from 1.76 to 4.10. Our results suggested that HBV mutations alone or in combination may be of clinical significance for predicting hepatocarcinogenesis.