Human hepatocellular carcinomas with a periportal phenotype have the lowest potential for early recurrence after curative resection

Abstract

Hepatocellular carcinomas (HCCs) exhibit a diversity of molecular phenotypes, raising major challenges in clinical management. HCCs detected by surveillance programs at an early stage are candidates for potentially curative therapies (local ablation, resection, or transplantation). In the long term, transplantation provides the lowest recurrence rates. Treatment allocation is based on tumor number, size, vascular invasion, performance status, functional liver reserve, and the prediction of early (<2 years) recurrence, which reflects the intrinsic aggressiveness of the tumor. Well‐differentiated, potentially low‐aggressiveness tumors form the heterogeneous molecular class of nonproliferative HCCs, characterized by an approximate 50% β‐catenin mutation rate. To define the clinical, pathological, and molecular features and the outcome of nonproliferative HCCs, we constructed a 1,133‐HCC transcriptomic metadata set and validated findings in a publically available 210‐HCC RNA sequencing set. We show that nonproliferative HCCs preserve the zonation program that distributes metabolic functions along the portocentral axis in normal liver. More precisely, we identified two well‐differentiated, nonproliferation subclasses, namely periportal‐type (wild‐type β‐catenin) and perivenous‐type (mutant β‐catenin), which expressed negatively correlated gene networks. The new periportal‐type subclass represented 29% of all HCCs; expressed a hepatocyte nuclear factor 4A–driven gene network, which was down‐regulated in mouse hepatocyte nuclear factor 4A knockout mice; were early‐stage tumors by Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program, and tumor–node–metastasis staging systems; had no macrovascular invasion; and showed the lowest metastasis‐specific gene expression levels and TP53 mutation rates. Also, we identified an eight‐gene periportal‐type HCC signature, which was independently associated with the highest 2‐year recurrence‐free survival by multivariate analyses in two independent cohorts of 247 and 210 patients. Conclusion: Well‐differentiated HCCs display mutually exclusive periportal or perivenous zonation programs. Among all HCCs, periportal‐type tumors have the lowest intrinsic potential for early recurrence after curative resection. (Hepatology 2017;66:1502–1518).

Argininosuccinate synthase 1 and periportal gene expression in sonic hedgehog hepatocellular adenomas

“…We showed that ASS1 belong to a set of genes from a periportal program expressed in sonic hedgehog HCA and downregulated in other molecular subgroups (Fig. ) . This data confirmed in human tumors the role of sonic hedgehog pathway in zonation previously observed in mouse models .…”

“…We hypothesized that GLI1 activation in shHCA could induce an alteration of the zonation program. In addition to ASS1 and ASL , we selected in the literature five other genes known to be expressed in periportal region ( HAL , SDS , GNMT , GLS2 and PCK1 ) and severn genes expressed in perivenous region ( CYP2E1 , CYP1A2 , RHBG , SLC22A12 , GLUL , LGR5 , AXIN2 ) . We assessed gene expression by quantitative reverse transcriptase polymerase chain reaction (RT–PCR) using Fluidigm technology and Taqman probes .…”

Non‐SMC condensin I complex subunit H enhances proliferation, migration, and invasion of hepatocellular carcinoma

“…Many studies have revealed that metastasis and recurrence are the most important reasons for the death of patients with HCC . Therefore, we examined the function of NCAPH in migration and invasion.…”

Metabolism‐associated molecular classification of hepatocellular carcinoma

“…Gene set variation analysis (GSVA) is a nonparametric and unsupervised gene set enrichment method that can estimate the score of certain pathway or signature based on transcriptomic data (Hanzelmann et al , ). The 115 metabolism‐relevant gene signatures and seven HCC progression‐relevant signatures were achieved from previously published studies (Desert et al , ; Rosario et al , ), and by using gsva r package, each sample received 120 scores corresponding to 115 metabolism signatures and seven progression‐relevant signatures. Subsequently, differential analysis was conducted based on the 113 metabolism scores using limma package in r software, and the signatures with an absolute log2 fold change (FC) > 0.2 (adjusted P < 0.05) were defined as differentially expressed signatures.…”