Genetic alterations in specific driver genes lead to disruption of cellular 
pathways and are critical events in the instigation and progression of 
hepatocellular carcinoma (HCC). As a prerequisite for individualized cancer 
treatment, we sought to characterize the landscape of recurrent somatic 
mutations in HCC. We performed whole-exome sequencing on 87 HCCs and matched 
normal adjacent tissues to an average coverage of 59×. The overall mutation rate 
was roughly two mutations per Mb, with a median of 45 nonsynonymous mutations 
that altered the amino acid sequence (range, 2-381). We found recurrent 
mutations in several genes with high transcript levels: TP53 (18%); CTNNB1 
(10%); KEAP1 (8%); C16orf62 (8%); MLL4 (7%); and RAC2 (5%). Significantly 
affected gene families include the nucleotide-binding domain and leucine-rich 
repeat-containing family, calcium channel subunits, and histone 
methyltransferases. In particular, the MLL family of methyltransferases for 
histone H3 lysine 4 were mutated in 20% of tumors.
CONCLUSION: The NFE2L2-KEAP1 and MLL pathways are recurrently mutated in 
multiple cohorts of HCC.