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

Background & Aims 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. Methods 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. Results 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. Conclusion 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. [ABSTRACT FROM AUTHOR]