Integrated genomic analyses of hepatocellular carcinoma

Hepatol Int. 2023 Feb;17(1):97-111. doi: 10.1007/s12072-022-10455-z. Epub 2022 Dec 6.

Abstract

Background: Genomic alterations play important roles in the development of cancer. We explored the impact of protein-coding genes and transcriptomic changes on clinical and molecular alterations in Taiwanese hepatocellular carcinoma (HCC) patients.

Methods: We analyzed 147 whole-exome sequencing and 100 RNA sequencing datasets of HCC and compared them with The Cancer Genome Atlas (TCGA)-Liver Hepatocellular Carcinoma cohort and develop a panel of 81 apoptosis-related genes for molecular classification.

Results: TERT (50%), TP53 (25%), CTNNB1 (14%), ARID1A (12%), and KMT2C (11%) were the most common genetic alterations of cancer-related genes. ALDH2 and KMT2C mutated at much higher frequencies in our cohort than in TCGA, whereas CTNNB1 was found only in 14% of our Taiwanese patients. A high germline mutation rate of ALDH2 in the APOBEC mutational signature and herb drug-related aristolochic acid-associated signature was also observed. Groups A and B of HCC were identified when we used apoptosis-related genes for molecular classification. The latter group, which had poorer survival outcomes, had significantly more aDC, CD4+ Tem, macrophages M2, NKT, plasma cells, and Th1 cells, and less CD4+ memory T cells, CD8+ Tcm, cDC, iDC, and Th2 cells, as well as more inter-chromosome fusion genes. Metatranscriptomic analysis revealed 54 cases of HBV infection. Moreover, we found that the main target gene of HBV integration is ALB.

Conclusions: Unique genomic alterations were observed in our Taiwanese HCC patients. Molecular classification using apoptosis-related genes could lead to new therapeutic approaches for HCC.

Keywords: APOBEC mutational signature; Apoptosis-related genes; Aristolochic acid; Fusion genes; Genomic alterations; Metatranscriptomic; Microenvironments; Molecular classification; Taiwanese hepatocellular carcinoma; Transcriptome.

MeSH terms

  • Aldehyde Dehydrogenase, Mitochondrial / genetics
  • Carcinoma, Hepatocellular* / genetics
  • Carcinoma, Hepatocellular* / pathology
  • Gene Expression Profiling
  • Genomics
  • Humans
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / pathology
  • Mutation

Substances

  • ALDH2 protein, human
  • Aldehyde Dehydrogenase, Mitochondrial