Title: Massive gene amplification drives paediatric hepatocellular carcinoma caused by bile salt export pump deficiency
Authors: Iannelli, Fabio ×
Collino, Agnese
Sinha, Shruti
Radaelli, Enrico
Nicoli, Paola
D'Antiga, Lorenzo
Sonzogni, Aurelio
Faivre, Jamila
Annick Buendia, Marie
Sturm, Ekkehard
Thompson, Richard J
Knisely, A S
Natoli, Gioacchino
Ghisletti, Serena
Ciccarelli, Francesca D #
Issue Date: 2014
Series Title: Nature communications vol:5 pages:3850
Article number: 10.1038/ncomms4850
Abstract: Hepatocellular carcinoma (HCC) is almost invariably associated with an underlying inflammatory state, whose direct contribution to the acquisition of critical genomic changes is unclear. Here we map acquired genomic alterations in human and mouse HCCs induced by defects in hepatocyte biliary transporters, which expose hepatocytes to bile salts and cause chronic inflammation that develops into cancer. In both human and mouse cancer genomes, we find few somatic point mutations with no impairment of cancer genes, but massive gene amplification and rearrangements. This genomic landscape differs from that of virus- and alcohol-associated liver cancer. Copy-number gains preferentially occur at late stages of cancer development and frequently target the MAPK signalling pathway, and in particular direct regulators of JNK. The pharmacological inhibition of JNK retards cancer progression in the mouse. Our study demonstrates that intrahepatic cholestasis leading to hepatocyte exposure to bile acids and inflammation promotes cancer through genomic modifications that can be distinguished from those determined by other aetiological factors.
ISSN: 2041-1723
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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