title: Loss of function of Notch1 identifies a poor prognosis group of early stage hepatocellular carcinoma following hepatectomy.
abstract: Notch1 has previously been implicated in the carcinogenesis of hepatocellular carcinoma (HCC). The present study aimed to investigate the prognostic value of Notch1 in early stage HCC patients after hepatectomy. The differential expression of Notch1 in paired tumor and non-tumorous tissue was evaluated by RT-PCR, western blotting and immunohistochemistry. The correlation between Notch1 expression and the surgical outcome of patients at BCLC stage 0/A and its ≤5 cm subgroup was retrospectively investigated in 206 patients from the Eastern Hepatobiliary Surgery Hospital (training cohort), and prospectively validated in 185 patients from the same center and retrospectively verified in 129 patients from the Fujian Medical University (validation cohort 1 and 2, respectively). Compared with paired non-tumorous tissues, loss of Notch1 was observed in tumor tissue. Patients with normal Notch1 had better prognosis than those with loss of Notch1 in the training cohort and ≤5 cm subgroup (time to recurrence: 38.5±6.1 vs. 16.0±3.2 months, P<0.001 and 53.0±6.1 vs. 21.7±3.5 months, P=0.004; 1-, 3-, 5-year survival rates: 91, 64 and 49% vs. 73, 31 and 22%, P<0.001 and 93, 71, 57% vs. 76, 39, 24%, P<0.001). Notch1 expression was an independent factor for recurrence and survival (hazard ratio: 1.901, 2.154; 2.038 and 2.337). Moreover, Notch1 status affected early tumor recurrence, as the 2-year recurrence rate was 61.2 vs. 26.9% (P<0.001) and 51.2 vs. 21.3% (P=0.002) in tumors with reduced or increased Notch1 expression in this cohort and subgroup. These results were fully confirmed by the study in our prospective and retrospective validation cohorts. The status of Notch1 is useful for predicting the prognosis of patients with early stage HCC undergoing hepatectomy.
authors.affiliation: Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, P.R. China.
authors.forename: Jing-Feng
authors.initials: JF
authors.lastname: Liu
authors.affiliation: Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, P.R. China.
authors.forename: Kui
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, P.R. China.
authors.forename: Zhen-Lin
authors.initials: ZL
authors.lastname: Yan
authors.affiliation: Department of Clinical Database, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, P.R. China.
authors.forename: Xu-Ying
authors.initials: XY
authors.lastname: Wan
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, P.R. China.
authors.forename: Ai-Min
authors.initials: AM
authors.lastname: Huang
authors.affiliation: Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, P.R. China.
authors.forename: Yi-Zhou
authors.initials: YZ
authors.lastname: Wang
authors.affiliation: Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, P.R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, P.R. China.
authors.forename: Le-Hua
authors.initials: LH
authors.lastname: Shi
authors.affiliation: Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, P.R. China.
authors.forename: Bing-Hua
authors.initials: BH
authors.lastname: Jiao
authors.affiliation: Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, P.R. China.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Shen
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006498:Hepatectomy; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D009367:Neoplasm Staging; D011379:Prognosis; D051881:Receptor, Notch1 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1