Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation

Camilla Pilati, Eric Letouzé, Jean Charles Nault, Sandrine Imbeaud, Anaïs Boulai, Julien Calderaro, Karine Poussin, Andrea Franconi, Gabrielle Couchy, Guillaume Morcrette, Maxime Mallet, Saïd Taouji, Charles Balabaud, Benoit Terris, Frédéric Canal, Valérie Paradis, Jean Yves Scoazec, Anne deMuret, Catherine Guettier, Paulette Bioulac-SageEric Chevet, Fabien Calvo, Jessica Zucman-Rossi

Research output: Contribution to journalArticlepeer-review

214 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)428-441
Number of pages14
JournalCancer Cell
Volume25
Issue number4
DOIs
Publication statusPublished - 14 Apr 2014
Externally publishedYes

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