Transcriptional profiling of pure fibrolamellar hepatocellular carcinoma reveals an endocrine signature.
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.


CONCLUSIONS
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.
Department of Medical Oncology, Beaujon University Hospital and INSERM U728, Clichy, France.
Gabriel G
GG
Malouf
Sylvie
S
Job
Valérie
V
Paradis
Monique
M
Fabre
Laurence
L
Brugières
Pierre
P
Saintigny
Laure
L
Vescovo
Jacques
J
Belghiti
Sophie
S
Branchereau
Sandrine
S
Faivre
Aurélien
A
de Reyniès
Eric
E
Raymond
D000328:Adult; D002116:Calcitonin / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D018734:Genes, erbB-2; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009496:Neurotensin / Q000235:genetics / Q000378:metabolism; D045664:Proprotein Convertase 1 / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D002116:Calcitonin; D009419:Nerve Tissue Proteins; D009496:Neurotensin; D045664:Proprotein Convertase 1; D018719:Erb-b2 Receptor Tyrosine Kinases; D011956:Receptors, Cell Surface; C462501:DNER protein, human