Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death, and the prognosis varies due to its high heterogeneity, systematic evaluation of HCC is mainly based on genomic and transcriptomic features, metabolomics-based classification has yet to be reported. Here we performed RNA-seq on 50 paired samples and metabolomics analysis on 72 paired samples of both normal and tumor tissues from HCC patients. Through unsupervised hierarchical cluster analysis with train and test data sets, metabolic and gene expression signatures were identified. We found that most fluxes related to glutamate are attenuated, except for the glutamate-proline pathway. Three subgroups were identified with distinct survival, clinical observations, and metabolic/gene signatures. S1 is characterized by a relatively poor prognosis, a low concentration of the degradation products of phosphatidylcholine and phosphatidylethanolamine, an enrichment of specific genes related to focal adhesion, and an upregulation of genes on chromosome 6q27. Beyond commonly downregulated metabolites, S2 tumors are largely characterized by few alterations in metabolites and genes, as well as low incidence of mutations/loss of heterozygosity, the metabolite signature of this group consists of hexoses and their phosphates, and the prognosis is the best, with a 5-year survival rate of greater than 80%. S3 is characterized by the worst survival (an approximately 20% 5-year survival rate), unsaturated fatty acid metabolites, an upregulation of specific genes involved in metastasis, and an upregulation of genes on chromosome 1q21. The metabolite-based classifications are more stable and reproducible, with each subgroup characterized by a distinct molecular signature and disease prognosis.

中文翻译：

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基于代谢组学的分类揭示了肝细胞癌的亚型

肝细胞癌（hepatocellular carcinoma，HCC）是癌症相关死亡的第二大原因，其预后因异质性高而异，对HCC的系统评价主要基于基因组学和转录组学特征，基于代谢组学的分类尚未见报道。在这里，我们对 50 个配对样本进行了 RNA-seq，并对来自 HCC 患者的正常组织和肿瘤组织的 72 个配对样本进行了代谢组学分析。通过对训练和测试数据集进行无监督层次聚类分析，确定了代谢和基因表达特征。我们发现与谷氨酸相关的大多数通量都减弱了，除了谷氨酸-脯氨酸途径。三个亚组被确定为具有不同的生存、临床观察和代谢/基因特征。S1 的特点是预后相对较差，低浓度的磷脂酰胆碱和磷脂酰乙醇胺的降解产物，与粘着斑相关的特定基因的富集，以及染色体 6q27 上基因的上调。除了常见的下调代谢物外，S2 肿瘤的主要特征是代谢物和基因的改变很少，以及突变发生率低/杂合性丢失，该组的代谢物特征由己糖及其磷酸盐组成，预后最好， 5年生存率大于80%。S3 的特征是最差的存活率（大约 20% 的 5 年存活率）、不饱和脂肪酸代谢物、参与转移的特定基因的上调以及染色体 1q21 上的基因上调。基于代谢物的分类更加稳定和可重复，