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Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Early diagnosis and treatment of HCC remain a key goal for improving patient survival. Chronic hepatitis B virus (HBV) infection is a major risk factor for HCC development. Pre-S mutants harboring deletions in HBV large surface antigen have been well demonstrated as HBV oncoproteins that dysregulate multiple signaling pathways in hepatocytes, leading to HCC formation. The presence of pre-S mutants in plasma represents important predictive and prognostic markers for HCC in patients with chronic HBV infection. However, the method to detect pre-S mutants remains to be optimized. In this study, we developed a platform, based on the next-generation sequencing (NGS) technology, for detection of pre-S mutants in plasma of HBV-related HCC patients. Compared to the current TA cloning-based analysis, the NGS-based analysis could detect pre-S deletion quantitatively, and the detection rate was significantly more sensitive in 49 plasma analyzed (McNemar’s paired proportion test, P value < 0.0001; simple kappa coefficient, κ = 0.29 (95% CI, 0.12 to 0.46)). Our data suggest that the NGS-based platform may hold a promise for improving the clinical application of pre-S mutants in serving as predictive and prognostic markers for HBV-related HCC.
Highlights
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide
Our previous studies have well demonstrated that pre-S mutants, which contain in-frame deletions in the pre-S1 and/or pre-S2 gene segments of hepatitis B virus (HBV) large surface antigen (LHBs) (Fig. 1), are HBV oncoproteins and can initiate multiple endoplasmic reticulum (ER) stress-related signaling pathways, contributing to growth advantages of hepatocytes and eventually HCC formation[11,12,13]
Pre-S mutants have emerged as important predictive markers for HCC risk in chronic HBV carriers as well as powerful prognostic markers for recurrence risk in HBV-related HCC patients following surgical resection[14,15,18,19,20]
Summary
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Early diagnosis and treatment of HCC remain a key goal for improving patient survival. The presence of pre-S mutants in liver tissues or blood carries a 5-fold higher risk of HCC development in patients with chronic HBV infection[14,15]. Several methods have been applied to detect the presence of pre-S mutants in chronic HBV carriers and HBV-related HCC patients, including the methods based on immunohistochemistry (IHC) staining of HBV surface antigen (HBsAg)[13,19], TA cloning and DNA sequencing following polymerase chain reaction (PCR) amplification of pre-S gene (including both pre-S1 and pre-S2 regions)[14,15,16], and the usage of Pre-S Gene Chip[17,20].
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