Format

Send to

Choose Destination
Hepatology. 2019 Jun 17. doi: 10.1002/hep.30811. [Epub ahead of print]

Clinical Impact of Genomic Diversity From Early to Advanced Hepatocellular Carcinoma.

Author information

1
Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Functional Genomics of Solid Tumors Laboratory, Paris, France.
2
Service d'Hépatologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France.
3
Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France.
4
Service d'Anatomopathologie, Hôpital Henri Mondor, Créteil, France.
5
Université Paris Est Créteil, Inserm U955, Team 18, Institut Mondor de Recherche Biomédicale, Créteil, France.
6
Service d'Anatomopathologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France.
7
Centre de Ressources Biologiques (BB-0033-00027) Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France.
8
University of Bordeaux, UMR1053 Bordeaux Research in Translational Oncology, BaRITOn, Bordeaux, France.
9
Service de Pathologie, Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
10
Service Hépato-Gastroentérologie et Oncologie Digestive, Centre Medico-Chirurgical Magellan, Hôpital Haut-Lévêque, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
11
Service d'Hépatogastroentérologie, Hôpital Henri Mondor, Université Paris Est Créteil, Créteil, France.
12
Service de Chirurgie Digestive, Centre Medico-Chirurgical Magellan, Hôpital Haut-Lévêque, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
13
Service d'Oncologie Médicale, Hôpital Beaujon, Assistance-Publique Hôpitaux de Paris, Clichy, France.
14
Service de Chirurgie Digestive, Hôpital Henri Mondor, Créteil, France.
15
Université Paris Est Créteil, Créteil, France.
16
Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY.
17
Liver Cancer Translational Research Laboratory, BCLC Group, IDIBAPS, CIBEREHD, Hospital Clinic, Universitat de Barcelona, Catalonia, Spain.
18
Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
19
Service de Radiologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France.
20
Hôpital Europeen Georges Pompidou, Assistance-Publique Hôpitaux de Paris, Paris, France.

Abstract

To date, genomic analyses of hepatocellular carcinoma (HCC) have been limited to early stages obtained from liver resection. We aim to describe the genomic profiling of HCC from early to advanced stages. We analyzed 801 HCC from 720 patients (410 resections, 137 transplantations, 122 percutaneous ablations, and 52 noncurative) for 190 gene expressions and for 31 gene mutations. Forty-one advanced HCC and 156 whole exome of Barcelona Clinic Liver Cancer (BCLC) 0/A were analyzed by whole-exome sequencing. Genomic profiling was correlated with tumor stages, clinical features, and survival. Our cohort included patients classified in BCLC stage 0 (9.4%), A (59.5%), B (16.2%), and C (14.9%). Among the overall 801 HCC, the most frequently mutated genes were telomerase reverse transcriptase (TERT) (58.1%), catenin beta 1 (CTNNB1) (30.7%), tumor protein 53 (TP53; 18.7%), AT-rich interaction domain 1A (ARID1A) (13%), albumin (11.4%), apolipoprotein B (APOB) (9.4%), and AXIN1 (9.2%). Advanced-stage HCC (BCLC B/C) showed higher frequencies of splicing factor 3b subunit 1 (SF3B1) (P = 0.0003), TP53 (P = 0.0006), and RB Transcriptional Corepressor 1 mutations (P = 0.03). G1-G6 transcriptomic classification and the molecular prognostic 5-gene score showed different distributions according to the stage of the disease and the type of treatment with an enrichment of G3 (P < 0.0001), poor prognostic score (P < 0.0001), and increased proliferation and dedifferentiation at the transcriptomic level in advanced HCC. The 5-gene score predicted survival in patients treated by resection (P < 0.0001) and ablation (P = 0.01) and in advanced HCC (P = 0.04). Twenty-two percent of advanced HCC harbored potentially druggable genetic alterations, and MET amplification was associated with complete tumor response in patients with advanced HCC treated by a specific MET inhibitor. Conclusion: Genomic analysis across the different stages of HCC revealed the mechanisms of tumor progression and helped to identify biomarkers of response to targeted therapies.

PMID:
31206197
DOI:
10.1002/hep.30811

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center