title: Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification.
abstract: Hepatic resection is the most curative treatment option for early-stage hepatocellular carcinoma, but is associated with a high recurrence rate, which exceeds 50% at 5 years after surgery. Understanding the genetic basis of hepatocellular carcinoma at surgically curable stages may enable the identification of new molecular biomarkers that accurately identify patients in need of additional early therapeutic interventions. Whole exome sequencing and copy number analysis was performed on 231 hepatocellular carcinomas (72% with hepatitis B viral infection) that were classified as early-stage hepatocellular carcinomas, candidates for surgical resection. Recurrent mutations were validated by Sanger sequencing. Unsupervised genomic analyses identified an association between specific genetic aberrations and postoperative clinical outcomes. Recurrent somatic mutations were identified in nine genes, including TP53, CTNNB1, AXIN1, RPS6KA3, and RB1. Recurrent homozygous deletions in FAM123A, RB1, and CDKN2A, and high-copy amplifications in MYC, RSPO2, CCND1, and FGF19 were detected. Pathway analyses of these genes revealed aberrations in the p53, Wnt, PIK3/Ras, cell cycle, and chromatin remodeling pathways. RB1 mutations were significantly associated with cancer-specific and recurrence-free survival after resection (multivariate P = 0.038 and P = 0.012, respectively). FGF19 amplifications, known to activate Wnt signaling, were mutually exclusive with CTNNB1 and AXIN1 mutations, and significantly associated with cirrhosis (P = 0.017).
  
  
  CONCLUSIONS
  RB1 mutations can be used as a prognostic molecular biomarker for resectable hepatocellular carcinoma. Further study is required to investigate the potential role of FGF19 amplification in driving hepatocarcinogenesis in patients with liver cirrhosis and to investigate the potential of anti-FGF19 treatment in these patients.
authors.affiliation: Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; Center for Cancer Genome Discovery, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; Department of Bioinformatics, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
authors.forename: Sung-Min
authors.initials: SM
authors.lastname: Ahn
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Jang
authors.forename: Ju Hyun
authors.initials: JH
authors.lastname: Shim
authors.forename: Deokhoon
authors.initials: D
authors.lastname: Kim
authors.forename: Seung-Mo
authors.initials: SM
authors.lastname: Hong
authors.forename: Chang Ohk
authors.initials: CO
authors.lastname: Sung
authors.forename: Daehyun
authors.initials: D
authors.lastname: Baek
authors.forename: Farhan
authors.initials: F
authors.lastname: Haq
authors.forename: Adnan Ahmad
authors.initials: AA
authors.lastname: Ansari
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Sung-Min
authors.initials: SM
authors.lastname: Chun
authors.forename: Seongmin
authors.initials: S
authors.lastname: Choi
authors.forename: Hyun-Jeung
authors.initials: HJ
authors.lastname: Choi
authors.forename: Jongkyu
authors.initials: J
authors.lastname: Kim
authors.forename: Sukjun
authors.initials: S
authors.lastname: Kim
authors.forename: Shin
authors.initials: S
authors.lastname: Hwang
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Lee
authors.forename: Jong-Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Wang-Rim
authors.initials: WR
authors.lastname: Jung
authors.forename: Hye Yoon
authors.initials: HY
authors.lastname: Jang
authors.forename: Eunho
authors.initials: E
authors.lastname: Yang
authors.forename: Wing-Kin
authors.initials: WK
authors.lastname: Sung
authors.forename: Nikki P
authors.initials: NP
authors.lastname: Lee
authors.forename: Mao
authors.initials: M
authors.lastname: Mao
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
authors.forename: Eunsil
authors.initials: E
authors.lastname: Yu
authors.forename: Han Chu
authors.initials: HC
authors.lastname: Lee
authors.forename: Gu
authors.initials: G
authors.lastname: Kong
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000601:surgery; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000601:surgery; D008297:Male; D008875:Middle Aged; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C117476:FGF19 protein, human; D016160:Retinoblastoma Protein; D005346:Fibroblast Growth Factors