BAP1 mutations define a homogeneous subgroup of hepatocellular carcinoma with fibrolamellar-like features and activated PKA

Théo Z. Hirsch, Ana Negulescu, Barkha Gupta, Stefano Caruso, Bénédicte Noblet, Gabrielle Couchy, Quentin Bayard, Léa Meunier, Guillaume Morcrette, Jean Yves Scoazec, Jean Frédéric Blanc, Giuliana Amaddeo, Jean Charles Nault, Paulette Bioulac-Sage, Marianne Ziol, Aurélie Beaufrère, Valérie Paradis, Julien Calderaro, Sandrine Imbeaud, Jessica Zucman-Rossi

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    46 Citations (Scopus)

    Résumé

    Background & Aims: DNAJB1-PRKACA fusion is a specific driver event in fibrolamellar carcinoma (FLC), a rare subtype of hepatocellular carcinoma (HCC) that occurs in adolescents and young adults. In older patients, molecular determinants of HCC with mixed histological features of HCC and FLC (mixed-FLC/HCC) remain to be discovered. Methods: A series of 151 liver tumors including 126 HCC, 15 FLC, and 10 mixed-FLC/HCC were analyzed by RNAseq and whole-genome- or whole-exome sequencing. Western blots were performed to validate genomic discoveries. Results were validated using the TCGA database. Results: Most of the mixed-FLC/HCC RNAseq clustered in a robust subgroup of 17 tumors, which all had mutations or translocations inactivating BAP1, the gene encoding BRCA1-associated protein-1. Like FLC, BAP1-HCC were significantly enriched in females, patients with a lack of chronic liver disease, and fibrotic tumors compared to non-BAP1 HCC. However, patients were older and had a poorer prognosis than those with FLC. BAP1 tumors were immune hot, showed progenitor features and did not show DNAJB1-PRKACA fusion, while almost none of these tumors had mutations in CTNNB1, TP53 and TERT promoter. In contrast, 80% of the BAP1 tumors showed a chromosome gain of PRKACA at 19p13, combined with a loss of PRKAR2A (coding for the inhibitory regulatory subunit of PKA) at 3p21, leading to a high PRKACA/PRKAR2A ratio at the mRNA and protein levels. Conclusion: We have characterized a subgroup of BAP1-driven HCC with fibrolamellar-like features and a dysregulation of the PKA pathway, which could be at the root of the clinical and histological similarities between BAP1 tumors and DNAJB1-PRKACA FLCs. Lay summary: Herein, we have defined a homogeneous subgroup of hepatocellular carcinomas in which the BAP1 gene is inactivated. This leads to the development of cancers with features similar to those of fibrolamellar carcinoma. These tumors more frequently develop in females without chronic liver disease or cirrhosis. The presence of PKA activation and T cell infiltrates suggest that these tumors could be treated with PKA inhibitors or immunomodulators.

    langue originaleAnglais
    Pages (de - à)924-936
    Nombre de pages13
    journalJournal of Hepatology
    Volume72
    Numéro de publication5
    Les DOIs
    étatPublié - 1 mai 2020

    Contient cette citation