ABSTRACT

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.

中文翻译：

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金属磷酸酯酶1，肝细胞癌恶性肿瘤和复发的新候选基因

摘要

背景

确定与肝细胞癌 (HCC) 复发相关的新的基于机制的预后基因的需求尚未得到满足，这些基因可以预测患者的预后并提供治疗目标。本研究旨在确定 HCC 中潜在的新型驱动基因和突变。

方法

使用从一名患有 HBV 诱导的肝硬化的 HCC 患者中提取的 5 个 DNA 样本的全外显子组测序，确定了导致 HCC 复发的单核苷酸变异 (SNV)。SNV 在原发性 HCC (n = 87)、复发性 HCC (n = 34) 和良性肝病伴肝硬化 (n = 43) 中得到验证。确定了候选基因，并检查了其在 HCC 发展和复发中的关联和功能。

结果

确定了 177 个 SNV，验证了 70 个 SNV。chr18_11897016上的MPPE1错义突变是原发性和复发性 HCC 组织中最常见的突变 (16.5%)，在复发性 HCC 中发生的频率高于原发性 HCC 或良性肝肿瘤组织。所述MPPE1突变显著与肝癌复发相关（P = 0.003），TNM分期（P = 0.002），和Child-Pugh分级（P = 0.039），并且是HCC复发（HR的独立危险因素= 1.969 ; 95% CI = 1.043–3.714, P= .037）。对存放在 GEO 和 TCGA 中的公开数据的分析表明，与相邻的非肿瘤组织相比，HCC 肿瘤样本中 MPPE1 的表达水平显着增加。在 HCC 细胞系中敲低 MPPE1 可显着抑制细胞增殖、迁移和侵袭，在体外诱导细胞周期停滞和凋亡，并在体内抑制裸鼠的异种移植肿瘤生长( P < .05)。

结论

MPPE1是一种与 HCC 恶性肿瘤和复发相关的新基因。