Identification of driver genes in hepatocellular carcinoma by exome sequencing.
UNLABELLED: 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.
Cleary, SP; Jeck, WR; Zhao, X; Chen, K; Selitsky, SR; Savich, GL; Tan, T-X; Wu, MC; Getz, G; Lawrence, MS; Parker, JS; Li, J; Powers, S; Kim, H; Fischer, S; Guindi, M; Ghanekar, A; Chiang, DY
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