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J Hepatol. 2017 May;66(5):952-961. doi: 10.1016/j.jhep.2017.01.010. Epub 2017 Jan 23.

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

Author information

1
Liver Cancer Translational Research Laboratory, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Catalonia, Spain; Mount Sinai Liver Cancer Program, (Divisions of Liver Diseases, Hematology and Medical Oncology, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
2
Mount Sinai Liver Cancer Program, (Divisions of Liver Diseases, Hematology and Medical Oncology, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
3
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA.
4
Liver Cancer Translational Research Laboratory, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Catalonia, Spain.
5
Liver Cancer Translational Research Laboratory, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Catalonia, Spain; Mount Sinai Liver Cancer Program, (Divisions of Liver Diseases, Hematology and Medical Oncology, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain. Electronic address: Josep.Llovet@mssm.edu.

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 biliary-derived 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)-β signaling and enrichment of inflammation-related and immune response signatures (p<0.001). Stem-cell tumors were characterized by spalt-like 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-β 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.

KEYWORDS:

Liver cancer; Molecular subclass; Progenitor-like origin; TGF-β signaling

PMID:
28126467
DOI:
10.1016/j.jhep.2017.01.010
[Indexed for MEDLINE]
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