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

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BAP1 mutations define a homogeneous subgroup of hepatocellular carcinoma with fibrolamellar-like features and activated PKA
Journal of Hepatology ( IF 26.8 ) Pub Date : 2020-05-01 , DOI: 10.1016/j.jhep.2019.12.006
Théo Z Hirsch ₁ , Ana Negulescu ₁ , Barkha Gupta ₁ , Stefano Caruso ₁ , Bénédicte Noblet ₁ , Gabrielle Couchy ₁ , Quentin Bayard ₁ , Léa Meunier ₁ , Guillaume Morcrette ₂ , Jean-Yves Scoazec ₃ , Jean-Frédéric Blanc ₄ , Giuliana Amaddeo ₅ , Jean-Charles Nault ₆ , Paulette Bioulac-Sage ₇ , Marianne Ziol ₈ , Aurélie Beaufrère ₉ , Valérie Paradis ₁₀ , Julien Calderaro ₁₁ , Sandrine Imbeaud ₁ , Jessica Zucman-Rossi ₁₂

Affiliation

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.
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.
Service d'anatomie et de cytologie pathologiques, Gustave Roussy Cancer Center, F-94800 Villejuif, France.
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.
Service d'Hépato-Gastro-Entérologie, Hôpital Henri Mondor, APHP, Université Paris Est Créteil, Inserm U955, Institut Mondor de Recherche Biomédicale, F-94010 Créteil, France.
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.
Service de Pathologie, Hôpital Pellegrin, CHU de Bordeaux, F-33076 Bordeaux, France; Université Bordeaux, Inserm, Research in Translational Oncology, BaRITOn, F-33076 Bordeaux, France.
Service d'Anatomie Pathologique, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, APHP, Université Sorbonne Paris Nord, F-93140 Bondy, France.
Service de pathologie, Hôpital Beaujon, APHP, F-92110 Clichy, France.
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.
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.
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.

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.

中文翻译：

BAP1 突变定义了具有纤维板层样特征和活化 PKA 的同质肝细胞癌亚组

背景和目的 DNAJB1-PRKACA 融合是纤维板层癌 (FLC) 的特定驱动事件，FLC 是一种罕见的肝细胞癌 (HCC) 亚型，发生在青少年和年轻人中。在老年患者中，具有 HCC 和 FLC（混合 FLC/HCC）混合组织学特征的 HCC 的分子决定因素仍有待发现。方法通过 RNAseq 和全基因组或全外显子组测序分析了一系列 151 例肝脏肿瘤，包括 126 例 HCC、15 例 FLC 和 10 例混合 FLC/HCC。进行蛋白质印迹以验证基因组学发现。使用 TCGA 数据库验证结果。结果大多数混合 FLC/HCC RNAseq 聚集在一个由 17 个肿瘤组成的强大亚组中，所有肿瘤都显示出突变或易位使编码 BRCA1 相关蛋白 1 的 BAP1 失活。与 FLC 相似，BAP1-HCC 在女性中显着富集，与非 BAP1-HCC 相比，肿瘤纤维化和慢性肝病的缺乏。然而，与 FLC 患者相比，患者年龄较大且预后较差。BAP1 肿瘤是免疫热的，表现出祖细胞特征，没有表现出 DNAJB1-PRKACA 融合，并且几乎都没有 CTNNB1、TP53 和 TERT 启动子的突变。相比之下，80% 的 BAP1 肿瘤在 19p13 显示 PRKACA 染色体增加，同时在 3p21 丢失 PRKAR2A（编码 PKA 的抑制性调节亚基），导致 mRNA 和蛋白质的 PRKACA/PRKAR2A 比率高水平。结论我们已经表征了 BAP1 驱动的 HCC 亚组，具有纤维板层样特征和 PKA 通路失调，这可能是 BAP1 肿瘤和 DNAJB1-PRKACA FLC 之间临床和组织学相似性的根源。

更新日期：2020-05-01

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