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

Gastroenterology. 2017 Mar;152(4):880-894.e6. doi: 10.1053/j.gastro.2016.11.042. Epub 2016 Dec 7.


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: Benign; HCC; SHH; Tumor Progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • CTNNB1 protein, human
  • Chromogranins
  • GLI1 protein, human
  • HNF1A protein, human
  • Hedgehog Proteins
  • Hepatocyte Nuclear Factor 1-alpha
  • IL6ST protein, human
  • INHBE protein, human
  • Neoplasm Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Zinc Finger Protein GLI1
  • beta Catenin
  • Cytokine Receptor gp130
  • Inhibin-beta Subunits
  • Protein-Tyrosine Kinases
  • FRK protein, human
  • JAK2 protein, human
  • Janus Kinase 2
  • TERT protein, human
  • Telomerase
  • GNAS protein, human
  • GTP-Binding Protein alpha Subunits, Gs