TY - JOUR
T1 - Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation
AU - Nault, Jean-Charles
AU - Couchy, Gabrielle
AU - Balabaud, Charles
AU - Morcrette, Guillaume
AU - Caruso, Stefano
AU - Blanc, Jean-Frederic
AU - Bacq, Yannick
AU - Calderaro, Julien
AU - Paradis, Valérie
AU - Ramos, Jeanne
AU - Scoazec, Jean-Yves
AU - Gnemmi, Viviane
AU - Sturm, Nathalie
AU - Guettier, Catherine
AU - Fabre, Monique
AU - Savier, Eric
AU - Chiche, Laurence
AU - Labrune, Philippe
AU - Selves, Janick
AU - Wendum, Dominique
AU - Pilati, Camilla
AU - Laurent, Alexis
AU - De Muret, Anne
AU - Le Bail, Brigitte
AU - Rebouissou, Sandra
AU - Imbeaud, Sandrine
AU - Bioulac-Sage, Paulette
AU - Letouzé, Eric
AU - Zucman-Rossi, Jessica
AU - GENTHEP Investigators
AU - Mazzaferro, Vincenzo
N1 - Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
PY - 2017/3
Y1 - 2017/3
N2 - BACKGROUND & AIMS: Hepatocellular adenomas (HCAs) are benign liver tumors that can be assigned to molecular subtypes based on inactivating mutations in hepatocyte nuclear factor 1A, activating mutations in β-catenin, or activation of inflammatory signaling pathways. We aimed to update the classification system for HCA and associate the subtypes with disease risk factors and complications.METHODS: We analyzed expression levels of 20 genes and sequenced exon regions of 8 genes (HNF1A, IL6ST, CTNNB1, FRK, STAT3, GNAS, JAK1, and TERT) in 607 samples of 533 HCAs from 411 patients, collected from 28 centers mainly in France from 2000 and 2014. We performed gene expression profile, RNA sequence, whole-exome and genome sequence, and immunohistochemical analyses of select samples. Molecular data were associated with risk factors, histopathology, bleeding, and malignant transformation.RESULTS: Symptomatic bleeding occurred in 14% of the patients (85% of cases were female, median age, 38 years); 7% of the nodules were borderline between HCA and hepatocellular carcinoma, and 3% of patients developed hepatocellular carcinoma from HCA. Based on molecular features, we classified HCA into 8 subgroups. One new subgroup, composed of previously unclassified HCA, represented 4% of HCAs overall and was associated with obesity and bleeding. These tumors were characterized by activation of sonic hedgehog signaling, due to focal deletions that fuse the promoter of INHBE with GLI1. Analysis of genetic heterogeneity among multiple HCAs, from different patients, revealed a molecular subtype field effect; multiple tumors had different mutations that deregulated similar pathways. Specific molecular subtypes of HCA associated with various HCA risk factors, including imbalances in estrogen or androgen hormones. Specific molecular subgroup of HCA with β-catenin and sonic hedgehog activation associated with malignant transformation and bleeding, respectively.CONCLUSIONS: Using sequencing and gene expression analyses, we identified a subgroup of HCA characterized by fusion of the INHBE and GLI1 genes and activation of sonic hedgehog pathway. Molecular subtypes of HCAs associated with different patients' risk factors for HCA, disease progression, and pathology features of tumors. This classification system might be used to select treatment strategies for patients with HCA.
AB - BACKGROUND & AIMS: Hepatocellular adenomas (HCAs) are benign liver tumors that can be assigned to molecular subtypes based on inactivating mutations in hepatocyte nuclear factor 1A, activating mutations in β-catenin, or activation of inflammatory signaling pathways. We aimed to update the classification system for HCA and associate the subtypes with disease risk factors and complications.METHODS: We analyzed expression levels of 20 genes and sequenced exon regions of 8 genes (HNF1A, IL6ST, CTNNB1, FRK, STAT3, GNAS, JAK1, and TERT) in 607 samples of 533 HCAs from 411 patients, collected from 28 centers mainly in France from 2000 and 2014. We performed gene expression profile, RNA sequence, whole-exome and genome sequence, and immunohistochemical analyses of select samples. Molecular data were associated with risk factors, histopathology, bleeding, and malignant transformation.RESULTS: Symptomatic bleeding occurred in 14% of the patients (85% of cases were female, median age, 38 years); 7% of the nodules were borderline between HCA and hepatocellular carcinoma, and 3% of patients developed hepatocellular carcinoma from HCA. Based on molecular features, we classified HCA into 8 subgroups. One new subgroup, composed of previously unclassified HCA, represented 4% of HCAs overall and was associated with obesity and bleeding. These tumors were characterized by activation of sonic hedgehog signaling, due to focal deletions that fuse the promoter of INHBE with GLI1. Analysis of genetic heterogeneity among multiple HCAs, from different patients, revealed a molecular subtype field effect; multiple tumors had different mutations that deregulated similar pathways. Specific molecular subtypes of HCA associated with various HCA risk factors, including imbalances in estrogen or androgen hormones. Specific molecular subgroup of HCA with β-catenin and sonic hedgehog activation associated with malignant transformation and bleeding, respectively.CONCLUSIONS: Using sequencing and gene expression analyses, we identified a subgroup of HCA characterized by fusion of the INHBE and GLI1 genes and activation of sonic hedgehog pathway. Molecular subtypes of HCAs associated with different patients' risk factors for HCA, disease progression, and pathology features of tumors. This classification system might be used to select treatment strategies for patients with HCA.
KW - Adenoma
KW - Adolescent
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Carcinoma, Hepatocellular
KW - Cell Transformation, Neoplastic
KW - Child
KW - Chromogranins
KW - Cytokine Receptor gp130
KW - Female
KW - GTP-Binding Protein alpha Subunits, Gs
KW - Gene Fusion
KW - Hedgehog Proteins
KW - Hemorrhage
KW - Hepatocyte Nuclear Factor 1-alpha
KW - Humans
KW - Inhibin-beta Subunits
KW - Janus Kinase 2
KW - Liver Neoplasms
KW - Male
KW - Middle Aged
KW - Mutation
KW - Neoplasm Proteins
KW - Protein-Tyrosine Kinases
KW - Risk Factors
KW - STAT3 Transcription Factor
KW - Sequence Analysis, RNA
KW - Signal Transduction
KW - Telomerase
KW - Transcriptome
KW - Young Adult
KW - Zinc Finger Protein GLI1
KW - beta Catenin
KW - Journal Article
U2 - 10.1053/j.gastro.2016.11.042
DO - 10.1053/j.gastro.2016.11.042
M3 - Article
C2 - 27939373
VL - 152
SP - 880-894.e6
JO - Gastroenterology
JF - Gastroenterology
SN - 0016-5085
IS - 4
ER -