title: TP53 and RET may serve as biomarkers of prognostic evaluation and targeted therapy in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is the most common malignancy of the liver. Genomic analysis is conducted to identify genetic alterations in driver genes which are all druggable targets for cancer therapy. In the present study, we performed an exome sequencing of 45 driver genes in 100 paired samples from HCC patients including tumors and matched adjacent normal tissues using Illumina HiSeq 2000 platform. Non-synonymous mutations were ascertained using the iPLEX MassARRAY system and Sanger sequencing. Clinicopathological relevance with genetic variations was assessed using SPSS software. The prognostic analyses of patients with gene mutation status were summarized using Kaplan-Meier curves. Sixty-one non-synonymous somatic mutations were identified in 43% of the HCC patients. The most frequent mutations were: TP53 (20%), RET (6%), PLCE1 (5%), PTEN (4%) and VEGFR2 (3%). Patients with mutations in TP53 had a lower overall survival (OS) (P=0.002) than those without mutations. Recurrent mutations in the Ret proto‑oncogene (RET) were associated with poor outcomes for both disease‑free survival (DFS) (P=0.028) and OS (P=0.001) in HCC patients. The mutational status of sorafenib-targeted genes were associated with decreased DFS (P=0.039), and decreased OS (P=0.15) without statistical significance. Mutual exclusion of TP53 and RET mutations were observed in the present study. In conclusion, patients with TP53 mutations, RET mutations and sorafenib-targeted gene mutations were demonstrated to be associated with poor HCC prognosis, which suggests that both TP53 and RET may serve as biomarkers of prognostic evaluation and targeted therapy in HCC.
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Song
authors.initials: S
authors.lastname: Ye
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Xin-Yi
authors.initials: XY
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China.
authors.forename: Xiao-Ge
authors.initials: XG
authors.lastname: Hu
authors.affiliation: Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China.
authors.forename: Tang
authors.initials: T
authors.lastname: Li
authors.affiliation: Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China.
authors.forename: Qiu-Ran
authors.initials: QR
authors.lastname: Xu
authors.affiliation: Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, Guangdong 518103, P.R. China.
authors.forename: Huan-Ming
authors.initials: HM
authors.lastname: Yang
authors.affiliation: Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China.
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Huang
authors.affiliation: Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D059472:Exome; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011379:Prognosis; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods*; D000077157:Sorafenib; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D010671:Phenylurea Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D009536:Niacinamide; D000077157:Sorafenib; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human