Wu Qiong, Wang Lingyi, Tsui Stephen Kwok-Wing
School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
Front Genet. 2022 Aug 23;13:970907. doi: 10.3389/fgene.2022.970907. eCollection 2022.
Hepatocellular carcinoma (HCC) is a primary malignancy with increasing incidence and poor prognosis. Heterogeneity originating from genomic instability is one of the critical reasons of poor outcomes. However, the studies of underlying mechanisms and pathways affected by mutations are still not intelligible. Currently, integrative molecular-level studies using multiomics approaches enable comprehensive analysis for cancers, which is pivotal for personalized therapy and mortality reduction. In this study, genomic and transcriptomic data of HCC are obtained from The Cancer Genome Atlas (TCGA) to investigate the affected coding and non-coding RNAs, as well as their regulatory network due to certain mutational signatures of HCC. Different types of RNAs have their specific enriched biological functions in mutational signature-specific HCCs, upregulated coding RNAs are predominantly associated with lipid metabolism-related pathways, and downregulated coding RNAs are enriched in axonogenesis for tumor microenvironment generation. Additionally, differentially expressed miRNAs are inclined to concentrate in cancer-related signaling pathways. Some of these RNAs also serve as prognostic factors that help predict the survival outcome of HCCs with certain mutational signatures. Furthermore, deregulation of competing endogenous RNA (ceRNA) regulatory network is identified, which suggests a potential therapy interference of miRNA activity for mutational signature-specific HCC. This study proposes a projection approach to reduce therapeutic complexity from genomic mutations to transcriptomic alterations. Through this method, we identify genes and pathways critical for mutational signature-specific HCC and further discover a series of prognostic markers indicating patient survival outcome.
肝细胞癌（HCC）是一种发病率不断上升且预后较差的原发性恶性肿瘤。源于基因组不稳定的异质性是导致不良预后的关键原因之一。然而，关于受突变影响的潜在机制和途径的研究仍不清楚。目前，使用多组学方法进行的整合分子水平研究能够对癌症进行全面分析，这对于个性化治疗和降低死亡率至关重要。在本研究中，从癌症基因组图谱（TCGA）获取HCC的基因组和转录组数据，以研究受影响的编码和非编码RNA，以及由于HCC的某些突变特征而形成的调控网络。不同类型的RNA在具有特定突变特征的HCC中具有其特定的富集生物学功能，上调的编码RNA主要与脂质代谢相关途径有关，而下调的编码RNA在肿瘤微环境生成的轴突发生中富集。此外，差异表达的miRNA倾向于集中在癌症相关信号通路中。其中一些RNA还作为预后因素，有助于预测具有特定突变特征的HCC的生存结果。此外，还发现了竞争性内源RNA（ceRNA）调控网络的失调，这表明对具有特定突变特征的HCC的miRNA活性可能存在治疗干扰。本研究提出了一种从基因组突变到转录组改变来降低治疗复杂性的预测方法。通过这种方法，我们确定了对具有特定突变特征的HCC至关重要的基因和途径，并进一步发现了一系列指示患者生存结果的预后标志物。
