TY - JOUR
T1 - Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation
AU - Pilati, Camilla
AU - Letouzé, Eric
AU - Nault, Jean Charles
AU - Imbeaud, Sandrine
AU - Boulai, Anaïs
AU - Calderaro, Julien
AU - Poussin, Karine
AU - Franconi, Andrea
AU - Couchy, Gabrielle
AU - Morcrette, Guillaume
AU - Mallet, Maxime
AU - Taouji, Saïd
AU - Balabaud, Charles
AU - Terris, Benoit
AU - Canal, Frédéric
AU - Paradis, Valérie
AU - Scoazec, Jean Yves
AU - deMuret, Anne
AU - Guettier, Catherine
AU - Bioulac-Sage, Paulette
AU - Chevet, Eric
AU - Calvo, Fabien
AU - Zucman-Rossi, Jessica
N1 - Funding Information:
We warmly thank Isabelle Desitter, Cécile Guichard, and Ichrafe Ben Maad for helpful participation in this work. We also thank Jean Saric, Christophe Laurent, Brigitte Le Bail, Anne Rullier, Laurence Chiche (CHU Bordeaux) and Jeanne Tran Van Nhieu, Daniel Cherqui, Daniel Azoulay (CHU Henri Mondor, Créteil), and the tumor bank of CHU Bordeaux and CHU Henri Mondor for contributing to the tissue collection. We thank Randall Moon (Howard Hughes Medical Institute, University of Washington) and Eric Fearon (Regents of the University of Michigan) who provided the plasmids. This work was supported by the INCa within the ICGC project and 2010-1-PL BIO-02-1, the Ligue Nationale Contre le Cancer (“Carte d’identité des tumeurs” program), the Association pour la recherche contre le Cancer, ARC (grant 3194), and the Réseau national CRB Foie and BioIntelligence (OSEO). C.P. was supported by a fellowship from MENRT and ARC and J.-C.N. was supported by a fellowship from Inca.
PY - 2014/4/14
Y1 - 2014/4/14
N2 - Hepatocellular adenomas (HCA) are benign liver tumors predominantly developed in women using oral contraceptives. Here, exome sequencing identified recurrent somatic FRK mutations that induce constitutive kinase activity, STAT3 activation, and cell proliferation sensitive to Src inhibitors. We also found uncommon recurrent mutations activating JAK1, gp130, or β-catenin. Chromosome copy number and methylation profiling revealed patterns that correlated with specific gene mutations and tumor phenotypes. Finally, integrative analysis of HCAs transformed to hepatocellular carcinoma revealed β-catenin mutation as an early alteration and TERT promoter mutations as associated with the last step of the adenoma-carcinoma transition. In conclusion, we identified the genomic diversity in benign hepatocyte proliferation, several therapeutic targets, and the key genomic determinants of the adenoma-carcinoma transformation sequence.
AB - Hepatocellular adenomas (HCA) are benign liver tumors predominantly developed in women using oral contraceptives. Here, exome sequencing identified recurrent somatic FRK mutations that induce constitutive kinase activity, STAT3 activation, and cell proliferation sensitive to Src inhibitors. We also found uncommon recurrent mutations activating JAK1, gp130, or β-catenin. Chromosome copy number and methylation profiling revealed patterns that correlated with specific gene mutations and tumor phenotypes. Finally, integrative analysis of HCAs transformed to hepatocellular carcinoma revealed β-catenin mutation as an early alteration and TERT promoter mutations as associated with the last step of the adenoma-carcinoma transition. In conclusion, we identified the genomic diversity in benign hepatocyte proliferation, several therapeutic targets, and the key genomic determinants of the adenoma-carcinoma transformation sequence.
UR - http://www.scopus.com/inward/record.url?scp=84898445933&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2014.03.005
DO - 10.1016/j.ccr.2014.03.005
M3 - Article
C2 - 24735922
AN - SCOPUS:84898445933
SN - 1535-6108
VL - 25
SP - 428
EP - 441
JO - Cancer Cell
JF - Cancer Cell
IS - 4
ER -