Hepatocellular carcinoma (HCC) is a disease with unique management complexity because it displays high heterogeneity of molecular phenotypes. We herein aimed to characterize the molecular features of HCC by the development of a classification system that was based on the gene expression profile of metabolic genes. Integrative analysis was performed with a metadata set featuring 371 and 231 HCC human samples from the Cancer Genome Atlas and the International Cancer Genome Consortium, respectively. All samples were linked with clinical information. RNA sequencing data of 2752 previously characterized metabolism-related genes were used for non-negative matrix factorization clustering, and three subclasses of HCC (C1, C2, and C3) were identified. We then analyzed the metadata set for metabolic signatures, prognostic value, transcriptome features, immune infiltration, clinical characteristics, and drug sensitivity of subclasses, and compared the resulting subclasses with previously published classifications. Subclass C1 displayed high metabolic activity, low α-fetoprotein (AFP) expression, and good prognosis. Subclass C2 was associated with low metabolic activities and displayed high expression of immune checkpoint genes, demonstrating drug sensitivity toward cytotoxic T-lymphocyte-associated protein-4 inhibitors and the receptor tyrosine kinase inhibitor cabozantinib. Subclass C3 displayed intermediate metabolic activity, high AFP expression level, and bad prognosis. Finally, a 90-gene classifier was generated to enable HCC classification. This study establishes a new HCC classification based on the gene expression profiles of metabolic genes, thereby furthering the understanding of the genetic diversity of human HCC.

中文翻译：

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肝细胞癌的代谢相关分子分类。

肝细胞癌（HCC）是一种具有独特管理复杂性的疾病，因为它显示出很高的分子表型异质性。我们在此旨在通过开发基于代谢基因的基因表达谱的分类系统来表征HCC的分子特征。使用元数据集进行综合分析，该元数据集分别包含来自癌症基因组图谱和国际癌症基因组协会的371和231 HCC人类样本。所有样品均与临床信息相关联。将2752个先前表征的代谢相关基因的RNA测序数据用于非负矩阵分解聚类，并鉴定出HCC的三个亚类（C1，C2和C3）。然后，我们分析了元数据集的代谢特征，预后价值，转录组特征，免疫浸润，临床特征和子类的药物敏感性，并将得到的子类与以前发表的分类进行比较。C1类表现出高代谢活性，低甲胎蛋白（AFP）表达和良好的预后。C2类与低代谢活动有关，并显示免疫检查点基因的高表达，表明对细胞毒性T淋巴细胞相关蛋白4抑制剂和受体酪氨酸激酶抑制剂卡波替尼具有药物敏感性。C3亚类表现出中等代谢活性，高AFP表达水平和不良预后。最终，生成了90个基因的分类器以实现HCC分类。这项研究基于代谢基因的基因表达谱建立了新的HCC分类，