Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation

Jean-Charles Nault; Gabrielle Couchy; Charles Balabaud; Guillaume Morcrette; Stefano Caruso; Jean-Frederic Blanc; Yannick Bacq; Julien Calderaro; Valérie Paradis; Jeanne Ramos; Jean-Yves Scoazec; Viviane Gnemmi; Nathalie Sturm; Catherine Guettier; Monique Fabre; Eric Savier; Laurence Chiche; Philippe Labrune; Janick Selves; Dominique Wendum; Camilla Pilati; Alexis Laurent; Anne De Muret; Brigitte Le Bail; Sandra Rebouissou; Sandrine Imbeaud; Paulette Bioulac-Sage; Eric Letouzé; Jessica Zucman-Rossi; GENTHEP Investigators; Vincenzo Mazzaferro

doi:10.1053/j.gastro.2016.11.042

Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation

Jean-Charles Nault, Gabrielle Couchy, Charles Balabaud, Guillaume Morcrette, Stefano Caruso, Jean-Frederic Blanc, Yannick Bacq, Julien Calderaro, Valérie Paradis, Jeanne Ramos, Jean-Yves Scoazec, Viviane Gnemmi, Nathalie Sturm, Catherine Guettier, Monique Fabre, Eric Savier, Laurence Chiche, Philippe Labrune, Janick Selves, Dominique WendumCamilla Pilati, Alexis Laurent, Anne De Muret, Brigitte Le Bail, Sandra Rebouissou, Sandrine Imbeaud, Paulette Bioulac-Sage, Eric Letouzé, Jessica Zucman-Rossi, GENTHEP Investigators, Vincenzo Mazzaferro

Fondazione IRCCS Istituto Nazionale dei Tumori

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	880-894.e6
Journal	Gastroenterology
Volume	152
Issue number	4
DOIs	https://doi.org/10.1053/j.gastro.2016.11.042
Publication status	Published - Mar 2017

Keywords

Adenoma
Adolescent
Adult
Aged
Aged, 80 and over
Carcinoma, Hepatocellular
Cell Transformation, Neoplastic
Child
Chromogranins
Cytokine Receptor gp130
Female
GTP-Binding Protein alpha Subunits, Gs
Gene Fusion
Hedgehog Proteins
Hemorrhage
Hepatocyte Nuclear Factor 1-alpha
Humans
Inhibin-beta Subunits
Janus Kinase 2
Liver Neoplasms
Male
Middle Aged
Mutation
Neoplasm Proteins
Protein-Tyrosine Kinases
Risk Factors
STAT3 Transcription Factor
Sequence Analysis, RNA
Signal Transduction
Telomerase
Transcriptome
Young Adult
Zinc Finger Protein GLI1
beta Catenin
Journal Article

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10.1053/j.gastro.2016.11.042

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Nault, J-C., Couchy, G., Balabaud, C., Morcrette, G., Caruso, S., Blanc, J-F., Bacq, Y., Calderaro, J., Paradis, V., Ramos, J., Scoazec, J-Y., Gnemmi, V., Sturm, N., Guettier, C., Fabre, M., Savier, E., Chiche, L., Labrune, P., Selves, J., ... Mazzaferro, V. (2017). Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation. Gastroenterology, 152(4), 880-894.e6. https://doi.org/10.1053/j.gastro.2016.11.042

Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation. / Nault, Jean-Charles; Couchy, Gabrielle; Balabaud, Charles; Morcrette, Guillaume; Caruso, Stefano; Blanc, Jean-Frederic; Bacq, Yannick; Calderaro, Julien; Paradis, Valérie; Ramos, Jeanne; Scoazec, Jean-Yves; Gnemmi, Viviane; Sturm, Nathalie; Guettier, Catherine; Fabre, Monique; Savier, Eric; Chiche, Laurence; Labrune, Philippe; Selves, Janick; Wendum, Dominique; Pilati, Camilla; Laurent, Alexis; De Muret, Anne; Le Bail, Brigitte; Rebouissou, Sandra; Imbeaud, Sandrine; Bioulac-Sage, Paulette; Letouzé, Eric; Zucman-Rossi, Jessica; GENTHEP Investigators ; Mazzaferro, Vincenzo.

In: Gastroenterology, Vol. 152, No. 4, 03.2017, p. 880-894.e6.

Research output: Contribution to journal › Article › peer-review

Nault, J-C, Couchy, G, Balabaud, C, Morcrette, G, Caruso, S, Blanc, J-F, Bacq, Y, Calderaro, J, Paradis, V, Ramos, J, Scoazec, J-Y, Gnemmi, V, Sturm, N, Guettier, C, Fabre, M, Savier, E, Chiche, L, Labrune, P, Selves, J, Wendum, D, Pilati, C, Laurent, A, De Muret, A, Le Bail, B, Rebouissou, S, Imbeaud, S, Bioulac-Sage, P, Letouzé, E, Zucman-Rossi, J, GENTHEP Investigators & Mazzaferro, V 2017, 'Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation', Gastroenterology, vol. 152, no. 4, pp. 880-894.e6. https://doi.org/10.1053/j.gastro.2016.11.042

Nault, Jean-Charles ; Couchy, Gabrielle ; Balabaud, Charles ; Morcrette, Guillaume ; Caruso, Stefano ; Blanc, Jean-Frederic ; Bacq, Yannick ; Calderaro, Julien ; Paradis, Valérie ; Ramos, Jeanne ; Scoazec, Jean-Yves ; Gnemmi, Viviane ; Sturm, Nathalie ; Guettier, Catherine ; Fabre, Monique ; Savier, Eric ; Chiche, Laurence ; Labrune, Philippe ; Selves, Janick ; Wendum, Dominique ; Pilati, Camilla ; Laurent, Alexis ; De Muret, Anne ; Le Bail, Brigitte ; Rebouissou, Sandra ; Imbeaud, Sandrine ; Bioulac-Sage, Paulette ; Letouzé, Eric ; Zucman-Rossi, Jessica ; GENTHEP Investigators ; Mazzaferro, Vincenzo. / Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation. In: Gastroenterology. 2017 ; Vol. 152, No. 4. pp. 880-894.e6.

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abstract = "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.",

keywords = "Adenoma, Adolescent, Adult, Aged, Aged, 80 and over, Carcinoma, Hepatocellular, Cell Transformation, Neoplastic, Child, Chromogranins, Cytokine Receptor gp130, Female, GTP-Binding Protein alpha Subunits, Gs, Gene Fusion, Hedgehog Proteins, Hemorrhage, Hepatocyte Nuclear Factor 1-alpha, Humans, Inhibin-beta Subunits, Janus Kinase 2, Liver Neoplasms, Male, Middle Aged, Mutation, Neoplasm Proteins, Protein-Tyrosine Kinases, Risk Factors, STAT3 Transcription Factor, Sequence Analysis, RNA, Signal Transduction, Telomerase, Transcriptome, Young Adult, Zinc Finger Protein GLI1, beta Catenin, Journal Article",

author = "Jean-Charles Nault and Gabrielle Couchy and Charles Balabaud and Guillaume Morcrette and Stefano Caruso and Jean-Frederic Blanc and Yannick Bacq and Julien Calderaro and Val{\'e}rie Paradis and Jeanne Ramos and Jean-Yves Scoazec and Viviane Gnemmi and Nathalie Sturm and Catherine Guettier and Monique Fabre and Eric Savier and Laurence Chiche and Philippe Labrune and Janick Selves and Dominique Wendum and Camilla Pilati and Alexis Laurent and {De Muret}, Anne and {Le Bail}, Brigitte and Sandra Rebouissou and Sandrine Imbeaud and Paulette Bioulac-Sage and Eric Letouz{\'e} and Jessica Zucman-Rossi and {GENTHEP Investigators} and Vincenzo Mazzaferro",

year = "2017",

month = mar,

doi = "10.1053/j.gastro.2016.11.042",

language = "English",

volume = "152",

pages = "880--894.e6",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "4",

}

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

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 -

Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation

Abstract

Keywords

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