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BAP1 mutations define a specific subgroup of hepatocellular carcinoma with fibrolamellar features and PKA activation Short title: BAP1 HCC have FLC features and activate PKA
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International audience. BACKGROUND AND AIMS:DNAJB1-PRKACA fusion is a specific driver event in fibrolamellar carcinoma (FLC), a rare subtype of hepatocellular carcinoma (HCC) occurring 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 genomics discoveries. Results were validated using the TCGA database.RESULTS:Most of the mixed-FLC/HCC RNAseq clustered in a robust subgroup of 17 tumors all showing mutation or translocation inactivating BAP1 that codes for the BRCA1 associated protein-1. Similar to FLC, BAP1-HCC were significantly enriched in female, tumor fibrosis and the lack of chronic liver disease when compared to non-BAP1-HCC. However, patients were older and with a poorer prognosis than FLC patients. BAP1 tumors were immune hot, showed progenitor features, did not show DNAJB1-PRKACA fusion and were almost all non-mutated for 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 bearing 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.
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