Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification

• DOI: 10.1016/j.jhep.2017.05.014
• Publication Date: 2017-05-20T07:47:18Z
• Authors: Julien Calderaro; Gabrielle Couchy; Sandrine Imbeaud; Giuliana Amaddeo; Eric Letouzé; Jean-Frédéric Blanc; Christophe Laurent; Yacine Hajji; Daniel Azoulay; Paulette Bioulac-...; Jean-Charles Nault; Jessica Zucman-Rossi
• Keywords: Male; 0301 basic medicine; Carcinoma, Hepatocellular; Gene Expression Profiling; Tumor Suppressor Proteins; Liver Neoplasms; High-Throughput Nucleotide Sequencing; Sequence Analysis, DNA; Middle Aged; Genes, p53; Tuberous Sclerosis Complex 1 Protein; 3. Good health; 03 medical and health sciences; Phenotype; Mutation; Tuberous Sclerosis Complex 2 Protein; Humans; Female; Promoter Regions, Genetic; Telomerase; beta Catenin

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.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.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.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.