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.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with an estimated 600, 000 newly diagnosed cases every year worldwide [1, 2].It is one of the most common virus- associated cancers known to be highly refractory to treatment and represents one of the leading causes of cancer death worldwide [1, 2]
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
We validated the mutations identified in a larger cohort of HCC patients by Sequenom MassARRAY platform. we found that the TP53 (R249S) mutation was found exclusively in tumor tissues occurring in 7.7% of the HCC patients (Supplementary Table 8)
Summary
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with an estimated 600, 000 newly diagnosed cases every year worldwide [1, 2]. It is one of the most common virus- associated cancers known to be highly refractory to treatment and represents one of the leading causes of cancer death worldwide [1, 2]. The common etiology factors for HCC include chronic infections with hepatitis B (HBV) or hepatitis C (HCV). Hepatitis B virus (HBV) infection is the major cause of HCC in China and remains the major etiological factor in the HBV epidemic regions of China, South Korea, Southeast Asia, and subSaharan Africa [3]. Previous studies of the pathogenesis of HCC have revealed genetic alterations and molecular characteristics in HBV-mediated HCC such as mutations in beta catenin (CTNNB1), CDKN2A, TP53 and AXIN1 [10,11,12,13], amplification of CCND1/FGF19 and MYC, HBV integration in TERT and MLL4 [14,15,16]
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