Théo Z Hirsch1, Ana Negulescu1, Barkha Gupta1, Stefano Caruso1, Bénédicte Noblet1, Gabrielle Couchy1, Quentin Bayard1, Léa Meunier1, Guillaume Morcrette2, Jean-Yves Scoazec3, Jean-Frédéric Blanc4, Giuliana Amaddeo5, Jean-Charles Nault6, Paulette Bioulac-Sage7, Marianne Ziol8, Aurélie Beaufrère9, Valérie Paradis10, Julien Calderaro11, Sandrine Imbeaud1, Jessica Zucman-Rossi12. 1. Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; Functional Genomics of Solid Tumors laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France. 2. Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; Functional Genomics of Solid Tumors laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France; Service de Pathologie Pédiatrique, APHP, Hôpital Robert Debré, F-75019 Paris, France. 3. Service d'anatomie et de cytologie pathologiques, Gustave Roussy Cancer Center, F-94800 Villejuif, France. 4. Service Hépato-Gastroentérologie et Oncologie Digestive, Hôpital Haut-Lévêque, CHU de Bordeaux, F-33000 Bordeaux, France; Service de Pathologie, Hôpital Pellegrin, CHU de Bordeaux, F-33076 Bordeaux, France; Université Bordeaux, Inserm, Research in Translational Oncology, BaRITOn, F-33076 Bordeaux, France. 5. Service d'Hépato-Gastro-Entérologie, Hôpital Henri Mondor, APHP, Université Paris Est Créteil, Inserm U955, Institut Mondor de Recherche Biomédicale, F-94010 Créteil, France. 6. Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; Functional Genomics of Solid Tumors laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France; Service d'Hépatologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, APHP, Universitô Sorbonne Paris Nord, F-93140 Bondy, France. 7. Service de Pathologie, Hôpital Pellegrin, CHU de Bordeaux, F-33076 Bordeaux, France; Université Bordeaux, Inserm, Research in Translational Oncology, BaRITOn, F-33076 Bordeaux, France. 8. Service d'Anatomie Pathologique, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, APHP, Université Sorbonne Paris Nord, F-93140 Bondy, France. 9. Service de pathologie, Hôpital Beaujon, APHP, F-92110 Clichy, France. 10. Service de pathologie, Hôpital Beaujon, APHP, F-92110 Clichy, France; Université de Paris, CNRS, Centre de Recherche sur l'Inflammation (CRI), Paris, F-75890, France. 11. Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; Functional Genomics of Solid Tumors laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France; Service d'Anatomopathologie, Hôpital Henri Mondor, APHP, Institut Mondor de Recherche Biomédicale, F-94010 Créteil, France. 12. Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; Functional Genomics of Solid Tumors laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France; Hôpital Européen Georges Pompidou, APHP, F-75015 Paris, France. Electronic address: jessica.zucman-rossi@inserm.fr.
Abstract
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.
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-BAP1HCC. However, patients were older and had a poorer prognosis than those with FLC. BAP1tumors 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 BAP1tumors 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 BAP1tumors 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.
Authors: Timothy A Dinh; Alan F Utria; Kevin C Barry; Rosanna Ma; Ghassan K Abou-Alfa; John D Gordan; Elizabeth M Jaffee; John D Scott; Jessica Zucman-Rossi; Allison F O'Neill; Mark E Furth; Praveen Sethupathy Journal: Nat Rev Gastroenterol Hepatol Date: 2022-02-21 Impact factor: 73.082
Authors: Mikel Marín-Baquero; Ángel Rivera-Calzada; Juan P Unfried; Nerea Razquin; Eva M Martín-Cuevas; Sara de Bragança; Clara Aicart-Ramos; Christopher McCoy; Laura Prats-Mari; Raquel Arribas-Bosacoma; Linda Lee; Stefano Caruso; Jessica Zucman-Rossi; Bruno Sangro; Gareth Williams; Fernando Moreno-Herrero; Oscar Llorca; Susan P Lees-Miller; Puri Fortes Journal: Cancer Res Date: 2021-07-28 Impact factor: 12.701
Authors: Jeffrey S Damrauer; Markia A Smith; Vonn Walter; Aatish Thennavan; Lisle E Mose; Sara R Selitsky; Katherine A Hoadley Journal: Commun Biol Date: 2021-10-04