Whole genome sequencing of matched tumor, adjacent non-tumor tissues and corresponding normal blood samples of hepatocellular carcinoma patients revealed dynamic changes of the mutations profiles during hepatocarcinogenesis

// Ruifang Mao 1, 2 , Jie Liu 2 , Guanfeng Liu 2 , Shanshan Jin 2 , Qingzhong Xue 3 , Liang Ma 2 , Yan Fu 4 , Na Zhao 2 , Jinliang Xing 5 , Lanjuan Li 1 , Yunqing Qiu 6 , Biaoyang Lin 1, 2, 7 1 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China 2 Systems Biology Division, Zhejiang-California International Nanosystems Institute (ZCNI), Zhejiang University, Hangzhou, Zhejiang Province, P.R. China 3 Departmant of Agronomy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, P. R. China 4 College of Animal Sciences, Zhejiang University, Hangzhou, P. R. China 5 State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi’an, China 6 The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China 7 Departmant of Urology, University of Washington, Seattle, WA, USA Correspondence to: Biaoyang Lin, email: Biaoylin@gmail.com Lanjuan Li, email: ljli@zju.edu.cn Keywords: hepatocellular carcinoma (HCC), whole genome sequencing, next-generation sequencing, mutations, hepatitis B virus (HBV) Received: August 19, 2016      Accepted: February 01, 2017      Published: February 17, 2017 ABSTRACT Hepatocellular carcinoma (HCC) has become the third most deadly disease worldwide and HBV is the major factor in Asia and Africa. We conducted 9 WGS (whole genome sequencing) analyses for matched samples of tumor, adjacent non-tumor tissues and normal blood samples of HCC patients from three HBV positive patients. We then validated the mutations identified in a larger cohort of 177 HCC patients. We found that the number of the unique somatic mutations (average of 59,136) in tumor samples is significantly less than that in adjacent non-tumor tissues (average 83, 633). We discovered that the TP53 R249S mutation occurred in 7.7% of the HCC patients, and it was significantly associated with poor diagnosis. In addition, we found that the L104P mutation in the VCX gene (Variable charge, X-linked) was absent in white blood cell samples, but present at 11.1% frequency in the adjacent tissues and increased to 14.6% in HCC tissues, suggesting that this mutation might be a tumor driver gene driving HCC carcinogenesis. Finally, we identified a TK1-RNU7 fusion, which would result in a deletion of 103 amino acids from its C-terminal. The frequencies of this fusion event decreased from the adjacent tissues (29.2%) to the tumors (16.7%), suggesting that a truncated thymidine Kinase1 (TK1) caused by the fusion event might be deleterious and be selected against during tumor progression. The three-way comparisons allow the identification of potential driver mutations of carcinogenesis. Furthermore, our dataset provides the research community a valuable dataset for identifying dynamic changes of mutation profiles and driver mutations for HCC.