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Title: Mixed hepatocellular cholangiocarcinoma tumors: Cholangiolocellular carcinoma is a distinct molecular entity
Author: Moeini, Agrin
Sia, Daniela
Zhang, Zhongyang
Campreciós Figueras, Genís
Stueck, Ashley
Dong, Hui
Montal, Robert
Torrens, Laura
Martinez Quetglas, Iris
Fiel, Maria Isabel
Hao, Ke
Villanueva, Augusto
Thung, Swan N.
Schwartz, Myron
Llovet i Bayer, Josep Maria
Keywords: Càncer de fetge
Genètica molecular humana
Factors de creixement
Liver cancer
Human molecular genetics
Growth factors
Issue Date: 23-Jan-2017
Publisher: Elsevier
Abstract: 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.
Note: Versió postprint del document publicat a:
It is part of: Journal of Hepatology, 2017, vol. 66, num. 5, p. 952-961
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ISSN: 0168-8278
Appears in Collections:Articles publicats en revistes (Medicina)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Publicacions de projectes de recerca finançats per la UE

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