Background: There is an unmet need to identify novel mechanism-based prognostic genes associated with hepatocellular carcinoma (HCC) recurrence that can predict patient outcomes and provide therapeutic targets. This study aims to identify potential novel driver genes and mutations in HCC.
Methods: Single nucleotide variations (SNVs) contributing to HCC recurrence were identified using whole-exome sequencing of 5 DNA samples extracted from a single HCC patient with HBV-induced cirrhosis. SNVs were verified in primary HCC (n = 87), recurrent HCC (n = 34), and benign liver disease with cirrhosis tissues (n = 43). A candidate gene was identified, and its association and function in HCC development and recurrence were examined.
Results: 177 SNVs were identified and 70 SNVs were verified. A MPPE1 missense mutation on chr18_11897016 was the most frequent mutation (16.5%) in primary and recurrent HCC tissues, occurring with a higher frequency in recurrent HCC than primary HCC or benign liver tumor tissues. The MPPE1 mutation was significantly associated with HCC recurrence (P = .003), TNM stage (P = .002), and Child-Pugh classification (P = .039), and was an independent risk factor for HCC recurrence (HR = 1.969; 95%CI = 1.043-3.714, P = .037). Analysis of publically available data deposited in the GEO and TCGA showed MPPE1 expression levels were significantly increased in HCC tumor samples compared to adjacent nontumor tissues. The knockdown of MPPE1 in HCC cell lines significantly inhibited cell proliferation, migration and invasion, induced cell cycle arrest and apoptosis in vitro, and inhibited xenograft tumor growth in nude mice in vivo (P < .05).
Conclusions: MPPE1 is a novel gene associated with HCC malignancy and recurrence.
Keywords: Metallophosphoesterase 1; hepatocellular carcinoma; tumor recurrence; whole-exome sequencing.