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Genomic portrait of resectable hepatocellular carcinomas: Implications of RB1 and FGF19 aberrations for patient stratification
Author(s) -
Ahn SungMin,
Jang Se Jin,
Shim Ju Hyun,
Kim Deokhoon,
Hong SeungMo,
Sung Chang Ohk,
Baek Daehyun,
Haq Farhan,
Ansari Adnan Ahmad,
Lee Sun Young,
Chun SungMin,
Choi Seongmin,
Choi HyunJeung,
Kim Jongkyu,
Kim Sukjun,
Hwang Shin,
Lee YoungJoo,
Lee Jongeun,
Jung Wangrim,
Jang Hye Yoon,
Yang Eunho,
Sung WingKin,
Lee Nikki P.,
Mao Mao,
Lee Charles,
ZucmanRossi Jessica,
Yu Eunsil,
Lee Han Chu,
Kong Gu
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27198
Subject(s) - hepatocellular carcinoma , fgf19 , cancer research , cdkn2a , hccs , sorafenib , cirrhosis , wnt signaling pathway , sanger sequencing , biology , medicine , oncology , cancer , mutation , gene , genetics , receptor , fibroblast growth factor
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). Conclusion: 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. (H epatology 2014;60:1971–1981)