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Transcriptional profiling of pure fibrolamellar hepatocellular carcinoma reveals an endocrine signature
Author(s) -
Malouf Gabriel G.,
Job Sylvie,
Paradis Valérie,
Fabre Monique,
Brugières Laurence,
Saintigny Pierre,
Vescovo Laure,
Belghiti Jacques,
Branchereau Sophie,
Faivre Sandrine,
Reyniès Aurélien,
Raymond Eric
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27018
Subject(s) - hepatocellular carcinoma , endocrine system , medicine , cancer research , pathology , oncology , hormone
Fibrolamellar hepatocellular carcinoma (FLC) is a rare subtype of liver cancer occurring mostly in children and young adults. We have shown that FLC comprises two separate entities: pure (p‐FLC) and mixed‐FLC (m‐FLC), differing in clinical presentation and course. We show that p‐FLCs have a distinct gene expression signature different from that of m‐FLCs, which have a signature similar to that of classical hepatocellular carcinomas. We found p‐FLC profiles to be unique among 263 profiles related to diverse tumoral and nontumoral liver samples. We identified two distinct molecular subgroups of p‐FLCs with different outcomes. Pathway analysis of p‐FLCs revealed ERBB2 overexpression and an up‐regulation of glycolysis, possibly leading to compensatory mitochondrial hyperplasia and oncocytic differentiation. Four of the sixteen genes most significantly overexpressed in p‐FLCs were neuroendocrine genes: prohormone convertase 1 (PCSK1); neurotensin; delta/notch‐like EGF repeat containing; and calcitonin. PCSK1 overexpression was validated by immunohistochemistry, yielding specific, diffuse staining of the protein throughout the cytoplasm, possibly corresponding to a functional form of this convertase. Conclusion : p‐FLCs have a unique transcriptomic signature characterized by the strong expression of specific neuroendocrine genes, suggesting that these tumors may have a cellular origin different from that of HCC. Our data have implications for the use of genomic profiling for diagnosis and selection of targeted therapies in patients with p‐FLC. (H epatology 2014;59:2228–2237)