Julien Calderaro1, Gabrielle Couchy2, Sandrine Imbeaud2, Giuliana Amaddeo3, Eric Letouzé2, Jean-Frédéric Blanc4, Christophe Laurent5, Yacine Hajji2, Daniel Azoulay6, Paulette Bioulac-Sage7, Jean-Charles Nault8, Jessica Zucman-Rossi9. 1. Inserm, UMR-1162, Functional Genomics of Solid Tumors, Equipe Labellisée Ligue Contre le Cancer, Université Paris Descartes, Université Paris Diderot, Université Paris 13, F-75010, France; Assistance Publique-Hôpitaux de Paris, Department of Pathology, CHU Henri Mondor, Créteil, France; Université Paris Est Créteil, Faculté de Médecine, Créteil, France. 2. Inserm, UMR-1162, Functional Genomics of Solid Tumors, Equipe Labellisée Ligue Contre le Cancer, Université Paris Descartes, Université Paris Diderot, Université Paris 13, F-75010, France. 3. Université Paris Est Créteil, Faculté de Médecine, Créteil, France; Assistance Publique-Hôpitaux de Paris, Department of Hepatology, CHU Henri Mondor, Créteil, France; Inserm U955, Team 18, Créteil, France. 4. Department of Hepatogastroenterology and Digestive Oncology, CHU Bordeaux, Hôpital Haut-Lévêque, 33600 Pessac, France; Inserm UMR 1053, Université de Bordeaux, 33076 Bordeaux, France. 5. Department of Digestive and Endocrine Surgery, CHU-Hôpitaux de Bordeaux, France. 6. Université Paris Est Créteil, Faculté de Médecine, Créteil, France; Department of Digestive and Hepatobiliary Surgery, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Henri Mondor, 94000 Créteil, France. 7. Inserm UMR 1053, Université de Bordeaux, 33076 Bordeaux, France; Department of Pathology, Pellegrin Hospital, CHU Bordeaux, Bordeaux 33076, France. 8. Inserm, UMR-1162, Functional Genomics of Solid Tumors, Equipe Labellisée Ligue Contre le Cancer, Université Paris Descartes, Université Paris Diderot, Université Paris 13, F-75010, France; Liver Unit, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France. 9. Inserm, UMR-1162, Functional Genomics of Solid Tumors, Equipe Labellisée Ligue Contre le Cancer, Université Paris Descartes, Université Paris Diderot, Université Paris 13, F-75010, France; Assistance Publique-Hôpitaux de Paris, Department of Oncology, Hôpital Européen Georges Pompidou, Paris, France. Electronic address: jessica.zucman-rossi@inserm.fr.
Abstract
BACKGROUND & AIMS: Our increasing understanding of hepatocellular carcinoma (HCC) biology holds promise for personalized care, however its translation into clinical practice requires a precise knowledge of its relationship to tumour phenotype. METHODS: We aimed at investigating molecular-phenotypic correlations in a large series of HCC. To this purpose, 343 surgically resected HCC samples were investigated by pathological review, immunohistochemistry, gene expression profiling and sequencing. RESULTS: CTNNB1 (40%) and TP53 (21%) mutations were mutually exclusive and defined two major groups of HCC characterized by distinct phenotypes. CTNNB1 mutated tumours were large (p=0.002), well-differentiated (p<0.001), cholestatic (p<0.001), with microtrabecular (p<0.001) and pseudoglandular (p<0.001) patterns and without inflammatory infiltrates (p<0.001). TP53 mutated tumours were poorly differentiated (p<0.001) with a compact pattern (p=0.02), multinucleated (p=0.01) and pleomorphic (p=0.02) cells and frequent vascular invasion (p=0.02). World Health Organization (WHO) classification of histological subtypes were also strongly related to molecular features. The scirrhous subtype was associated with TSC1/TSC2 mutations (p=0.005), epithelial-to-mesenchymal transition and a progenitor expression profile. The steatohepatitic subtype showed frequent IL-6/JAK/STAT activation without CTNNB1, TERT and TP53 pathway alterations (p=0.01). Pathological review identified a novel subtype, designated as "macrotrabecular-massive" associated with poor survival (p<0.001), high alpha-fetoprotein serum level (p=0.02), vascular invasion (p<0.001), TP53 mutations (p<0.001) and FGF19 amplifications (p=0.02), features also validated in The Cancer Genome Atlas (TCGA) data. Finally, integration of HCC pathological characteristics with its transcriptomic classification showed phenotypically distinct tumour subclasses closely related to G1-G6 subgroups. CONCLUSION: HCC phenotypes are tightly associated with gene mutations and transcriptomic classification. These findings may help in translating our knowledge of HCC biology into clinical practice. Lay summary: HCC is a very heterogenous tumour, both at the pathological and molecular levels. We show here that HCC phenotype is tightly associated to its molecular alterations and underlying oncogenic pathways.
BACKGROUND & AIMS: Our increasing understanding of hepatocellular carcinoma (HCC) biology holds promise for personalized care, however its translation into clinical practice requires a precise knowledge of its relationship to tumour phenotype. METHODS: We aimed at investigating molecular-phenotypic correlations in a large series of HCC. To this purpose, 343 surgically resected HCC samples were investigated by pathological review, immunohistochemistry, gene expression profiling and sequencing. RESULTS:CTNNB1 (40%) and TP53 (21%) mutations were mutually exclusive and defined two major groups of HCC characterized by distinct phenotypes. CTNNB1 mutated tumours were large (p=0.002), well-differentiated (p<0.001), cholestatic (p<0.001), with microtrabecular (p<0.001) and pseudoglandular (p<0.001) patterns and without inflammatory infiltrates (p<0.001). TP53 mutated tumours were poorly differentiated (p<0.001) with a compact pattern (p=0.02), multinucleated (p=0.01) and pleomorphic (p=0.02) cells and frequent vascular invasion (p=0.02). World Health Organization (WHO) classification of histological subtypes were also strongly related to molecular features. The scirrhous subtype was associated with TSC1/TSC2 mutations (p=0.005), epithelial-to-mesenchymal transition and a progenitor expression profile. The steatohepatitic subtype showed frequent IL-6/JAK/STAT activation without CTNNB1, TERT and TP53 pathway alterations (p=0.01). Pathological review identified a novel subtype, designated as "macrotrabecular-massive" associated with poor survival (p<0.001), high alpha-fetoprotein serum level (p=0.02), vascular invasion (p<0.001), TP53 mutations (p<0.001) and FGF19 amplifications (p=0.02), features also validated in The Cancer Genome Atlas (TCGA) data. Finally, integration of HCC pathological characteristics with its transcriptomic classification showed phenotypically distinct tumour subclasses closely related to G1-G6 subgroups. CONCLUSION:HCC phenotypes are tightly associated with gene mutations and transcriptomic classification. These findings may help in translating our knowledge of HCC biology into clinical practice. Lay summary: HCC is a very heterogenous tumour, both at the pathological and molecular levels. We show here that HCC phenotype is tightly associated to its molecular alterations and underlying oncogenic pathways.
Authors: Chow Hiang Ang; Shih Han Hsu; Fusheng Guo; Chong Teik Tan; Victor C Yu; Jane E Visvader; Pierce K H Chow; Nai Yang Fu Journal: Proc Natl Acad Sci U S A Date: 2019-09-05 Impact factor: 11.205