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Glutamine synthetase-negative hepatocellular carcinoma has better prognosis and response to sorafenib treatment after hepatectomy

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Chinese Medical Journal 2023年第17期136卷 2066-2076页

作者： Mingyang Shao Qing Tao Yahong Xu Qing Xu Yuke Shu Yuwei Chen Junyi Shen Yongjie Zhou Zhenru Wu Menglin Chen Jiayin Yang Yujun Shi Tianfu Wen Hong Bu Institute of Clinical Pathology Key Laboratory of Transplant Engineering and ImmunologyNHCWest China HospitalSichuan UniversityChengduSichuan 610041China Laboratory of Liver Transplantation Frontiers Science Center for Disease-Related Molecular NetworkWest China HospitalSichuan UniversityChengduSichuan 610041China Department of Liver Surgery West China HospitalSichuan UniversityChengduSichuan 610041China Department of Pathology West China HospitalSichuan UniversityChengduSichuan 610041China

Background:Glutamine synthetase(GS)and arginase 1(Arg1)are widely used pathological markers that discriminate hepatocellular carcinoma(HCC)from intrahepatic cholangiocarcinoma;however,their clinical significance in HCC remains unclear.Methods:We retrospectively analyzed 431 HCC patients:251 received hepatectomy alone,and the other 180 received sorafenib as adjuvant treatment after hepatectomy.Expression of GS and Arg1 in tumor specimens was evaluated using immunostaining.mRNA sequencing and immunostaining to detect progenitor markers(cytokeratin 19[CK19]and epithelial cell adhesion molecule[EpCAM])and mutant TP53 were also conducted.Results:Up to 72.4%(312/431)of HCC tumors were GS positive(GS+).Of the patients receiving hepatectomy alone,GS negative(GS-)patients had significantly better overall survival(OS)and recurrence-free survival(RFS)than GS+patients;negative expression of Arg1,which is exclusively expressed in GS-hepatocytes in the healthy liver,had a negative effect on prognosis.Of the patients with a high risk of recurrence who received additional sorafenib treatment,GS-patients tended to have better RFS than GS+patients,regardless of the expression status of Arg1.GS+HCC tumors exhibit many features of the established proliferation molecular stratification subtype,including poor differentiation,high alpha-fetoprotein levels,increased progenitor tumor cells,TP53 mutation,and upregulation of multiple tumor-related signaling pathways.Conclusions:GS-HCC patients have a better prognosis and are more likely to benefit from sorafenib treatment after hepatectomy.Immunostaining of GS may provide a simple and applicable approach for HCC molecular stratification to predict prognosis and guide targeted therapy.

关键词： Hepatocellular carcinoma Glutamine synthetase molecular stratification Targeted therapy

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