Research Papers:

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, Jie Liu, Guanfeng Liu, Shanshan Jin, Qingzhong Xue, Liang Ma, Yan Fu, Na Zhao, Jinliang Xing, Lanjuan Li, Yunqing Qiu and Biaoyang Lin _

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Oncotarget. 2017; 8:26185-26199. https://doi.org/10.18632/oncotarget.15428

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Ruifang Mao1,2, Jie Liu2, Guanfeng Liu2, Shanshan Jin2, Qingzhong Xue3, Liang Ma2, Yan Fu4, Na Zhao2, Jinliang Xing5, Lanjuan Li1, Yunqing Qiu6, Biaoyang Lin1,2,7

1Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

2Systems Biology Division, Zhejiang-California International Nanosystems Institute (ZCNI), Zhejiang University, Hangzhou, Zhejiang Province, P.R. China

3Departmant of Agronomy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, P. R. China

4College of Animal Sciences, Zhejiang University, Hangzhou, P. R. China

5State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi’an, China

6The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

7Departmant of Urology, University of Washington, Seattle, WA, USA

Correspondence to:

Biaoyang Lin, email: [email protected]

Lanjuan Li, email: [email protected]

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


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.

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