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 - Archive ouverte HAL Access content directly
Journal Articles Journal of Hepatology Year : 2019

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

(1, 2) , (1, 2) , (1, 2) , (1, 2) , (1, 2) , (1, 2) , (1, 2) , (1, 2) , (2, 1, 3) , (4) , (5, 6, 7) , (8) , (1, 2, 9) , (7, 6) , (10) , (11) , (11, 12) , (1, 2, 13) , (1, 2) , (1, 2, 14)
1
2
3
4
5
6
7
8
9
10
11
12
13
14

Abstract

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.
Fichier principal
Vignette du fichier
Hirsch.et.al_revised_HAL.pdf (4.69 Mo) Télécharger le fichier
Origin : Files produced by the author(s)
Loading...

Dates and versions

inserm-02458837 , version 1 (29-01-2020)

Identifiers

Cite

Theo Hirsch, Ana Negulescu, Barkha Gupta, Stefano Caruso, Bénédicte Noblet, et al.. 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. Journal of Hepatology, 2019, ⟨10.1016/j.jhep.2019.12.006⟩. ⟨inserm-02458837⟩
504 View
790 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More