Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

TLDR

Liver cancer ranks second in global cancer mortality and currently has few effective treatment options. The study performed whole‑exome sequencing and copy‑number profiling on 363 HCC tumors, and integrated DNA methylation, RNA, miRNA, and proteomic data from 196 tumors. Integrated genomic, epigenomic, transcriptomic, and proteomic analyses revealed recurrent mutations in LZTR1, EEF1A1, SF3B1, SMARCA4, and metabolic‑reprogramming genes ALB, APOB, CPS1, defined three HCC subtypes with distinct prognoses, identified a p53‑target expression signature linked to poor survival, and highlighted actionable targets such as WNT, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoints CTLA‑4, PD‑1, and PD‑L1.

Abstract

Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy number analyses, and we analyzed 196 HCC cases by DNA methylation, RNA, miRNA, and proteomic expression also. DNA sequencing and mutation analysis identified significantly mutated genes, including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or downregulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.