title: Identification of driver genes in hepatocellular carcinoma by exome sequencing.
abstract: 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.
  
  
  CONCLUSIONS
  The NFE2L2-KEAP1 and MLL pathways are recurrently mutated in multiple cohorts of HCC.
authors.affiliation: Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Cleary
authors.forename: William R
authors.initials: WR
authors.lastname: Jeck
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Zhao
authors.forename: Kui
authors.initials: K
authors.lastname: Chen
authors.forename: Sara R
authors.initials: SR
authors.lastname: Selitsky
authors.forename: Gleb L
authors.initials: GL
authors.lastname: Savich
authors.forename: Ting-Xu
authors.initials: TX
authors.lastname: Tan
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wu
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.forename: Jinyu
authors.initials: J
authors.lastname: Li
authors.forename: Scott
authors.initials: S
authors.lastname: Powers
authors.forename: Hyeja
authors.initials: H
authors.lastname: Kim
authors.forename: Sandra
authors.initials: S
authors.lastname: Fischer
authors.forename: Maha
authors.initials: M
authors.lastname: Guindi
authors.forename: Anand
authors.initials: A
authors.lastname: Ghanekar
authors.forename: Derek Y
authors.initials: DY
authors.lastname: Chiang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D059472:Exome; D005260:Female; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D000072019:Kelch-Like ECH-Associated Protein 1; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; C497422:KMT2A protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase