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