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dc.contributor.author | Moeini, Agrin |
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dc.contributor.author | Sia, Daniela |
dc.contributor.author | Zhang, Zhongyang |
dc.contributor.author | Campreciós Figueras, Genís |
dc.contributor.author | Stueck, Ashley |
dc.contributor.author | Dong, Hui |
dc.contributor.author | Montal, Robert |
dc.contributor.author | Torrens, Laura |
dc.contributor.author | Martínez Quetglas, Iris |
dc.contributor.author | Fiel, Maria Isabel |
dc.contributor.author | Hao, Ke |
dc.contributor.author | Villanueva, Augusto |
dc.contributor.author | Thung, Swan N. |
dc.contributor.author | Schwartz, Myron |
dc.contributor.author | Llovet i Bayer, Josep Maria |
dc.date | 2018-03-01T17:55:20Z |
dc.date | 2017-01-23 |
dc.date | 2018-03-01T17:55:20Z |
dc.identifier | 0168-8278 |
dc.identifier | 677365 |
dc.identifier | 28126467 |
dc.identifier.uri | http://hdl.handle.net/2445/120387 |
dc.description | 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. |
dc.format | 39 p. |
dc.format | application/pdf |
dc.language | eng |
dc.publisher | Elsevier |
dc.relation | Versió postprint del document publicat a: https://doi.org/10.1016/j.jhep.2017.01.010 |
dc.relation | Journal of Hepatology, 2017, vol. 66, num. 5, p. 952-961 |
dc.relation | https://doi.org/10.1016/j.jhep.2017.01.010 |
dc.relation | info:eu-repo/grantAgreement/EC/H2020/667273/EU//HEP-CAR |
dc.relation | info:eu-repo/grantAgreement/EC/FP7/259744/EU//HEPTROMIC |
dc.rights | cc-by-nc-nd (c) Elsevier, 2017 |
dc.rights | http://creativecommons.org/licenses/by-nc-nd/3.0/es |
dc.rights | info:eu-repo/semantics/openAccess |
dc.subject | Càncer de fetge |
dc.subject | Genètica molecular humana |
dc.subject | Factors de creixement |
dc.subject | Liver cancer |
dc.subject | Human molecular genetics |
dc.subject | Growth factors |
dc.title | Mixed hepatocellular cholangiocarcinoma tumors: Cholangiolocellular carcinoma is a distinct molecular entity |
dc.type | info:eu-repo/semantics/article |
dc.type | info:eu-repo/semantics/acceptedVersion |