Mixed hepatocellular cholangiocarcinoma tumors: Cholangiolocellular carcinoma is a distinct molecular entity

JOURNAL OF HEPATOLOGY

卷:66

Article

Moeini, Agrin^1,2  Sia, Daniela²  Zhang, Zhongyang^3,4  Camprecios, Genis²  Stueck, Ashley²  Dong, Hui¹  Montal, Robert¹  Torrens, Laura¹  Martinez-Quetglas, Iris¹  Fiel, M. Isabel²  Hao, Ke^3,4  Villanueva, Augusto²  Thung, Swan N.²  Schwartz, Myron E.²  Llovet, Josep M.^1,2,5 

[1] Univ Barcelona, Liver Canc Translat Res Lab, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Liver Unit,Hosp Clin,CIBERehd, Barcelona, Catalonia, Spain

[2] Icahn Sch Med Mt Sinai, Mt Sinai Liver Canc Program, Recanati Miller Transplantat Inst, Div Liver Dis Hematol & Med Oncol,Dept Med,Tisch, Madison Ave 1425,11F-70,Box 1123, New York, NY 10029 USA

[3] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, Madison Ave 1425,11F-70,Box 1123, New York, NY 10029 USA

[4] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Madison Ave 1425,11F-70,Box 1123, New York, NY 10029 USA

[5] Inst Catalana Recerca & Estudis Avancats, Barcelona, Catalonia, Spain

关键词: Liver cancer;    Molecular subclass;    Progenitor-like origin;    TGF-beta signaling;   

DOI  :  10.1016/j.jhep.2017.01.010

来源: Elsevier

【 摘 要 】

Background & Aims: Mixed hepatocellular cholangiocarcinoma (HCC-CCA) is a rare and poorly understood type of primary liver cancer. We aimed to perform a comprehensive molecular characterization of this malignancy. Methods: Gene expression profiling, DNA copy number detection, and exome sequencing using formalin-fixed samples from 18 patients with mixed HCC-CCA were performed, encompassing the whole histological spectrum of the disease. Comparative genomic analysis was carried out, using independent datasets of HCC (n = 164) and intrahepatic cholangiocarcinoma (iCCA) (n = 149). Results: Integrative genomic analysis of HCC-CCAs revealed that cholangiolocellular carcinoma (CLC) represents a distinct biliaryderived entity compared with the stem-cell and classical types. CLC tumors were neural cell adhesion molecule (NCAM) positive (6/6 vs. 1/12, p < 0.001), chromosomally stable (mean chromosomal aberrations 5.7 vs. 14.1, p = 0.008), showed significant upregulation of transforming growth factor (TGF)-beta signaling and enrichment of inflammation-related and immune response signatures (p < 0.001). Stem-cell tumors were characterized by spaltlike transcription factor 4 (SALL4) positivity (6/8 vs. 0/10, p < 0.001), enrichment of progenitor-like signatures, activation of specific oncogenic pathways (i.e., MYC and insulin-like growth factor [IGF]), and signatures related to poor clinical outcome. In the classical type, there was a significant correlation in the copy number variation of the iCCA and HCC components, suggesting a clonal origin. Exome sequencing revealed an average of 63 non-synonymous mutations per tumor (2 mean driver mutations per tumor). Among those, TP53 was the most frequently mutated gene (6/21, 29%) in HCC-CCAs. Conclusions: Mixed HCC-CCA represents a heterogeneous group of tumors, with the stem-cell type characterized by features of poor prognosis, and the classical type with common lineage for HCC and iCCA components. CLC stands alone as a distinct biliary-derived entity associated with chromosomal stability and active TGF-b signaling. Lay summary: Molecular analysis of mixed hepatocellular cholangiocarcinoma (HCC-CCA) showed that cholangiolocellular carcinoma (CLC) is distinct and biliary in origin. It has none of the traits of hepatocellular carcinoma (HCC). However, within mixed HCC-CCA, stem-cell type tumors shared an aggressive nature and poor outcome, whereas the classic type showed a common cell lineage for both the HCC and the intrahepatic CCA component. The pathological classification of mixed HCC-CCA should be redefined because of the new molecular data provided. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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