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

Desert, Romain, Rohart, Florian, Canal, Frederic, Sicard, Marie, Desille, Mireille, Renaud, Stephanie, Turlin, Bruno, Bellaud, Pascale, Perret, Christine, Clement, Bruno, Le Cao, Kim-Anh and Musso, Orlando (2017) Human hepatocellular carcinomas with a periportal phenotype have the lowest potential for early recurrence after curative resection. Hepatology, 66 5: 1502-1518. doi:10.1002/hep.29254


Author Desert, Romain
Rohart, Florian
Canal, Frederic
Sicard, Marie
Desille, Mireille
Renaud, Stephanie
Turlin, Bruno
Bellaud, Pascale
Perret, Christine
Clement, Bruno
Le Cao, Kim-Anh
Musso, Orlando
Title Human hepatocellular carcinomas with a periportal phenotype have the lowest potential for early recurrence after curative resection
Journal name Hepatology   Check publisher's open access policy
ISSN 0270-9139
1527-3350
Publication date 2017-11-01
Year available 2017
Sub-type Article (original research)
DOI 10.1002/hep.29254
Open Access Status Not yet assessed
Volume 66
Issue 5
Start page 1502
End page 1518
Total pages 17
Place of publication Hoboken, NJ, United States
Publisher John Wiley & Sons
Language eng
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% b-catenin mutation rate. To define the clinical, pathological, and molecular features and the outcome of nonproliferative HCCs, we constructed a 1,133HCC 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 b-catenin) and perivenous-type (mutant b-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 downregulated 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.
Keyword Fatty liver disease
Magnetic resonance elastography
Chronic hepatitis C
Simple noninvasive index
Transient elastography
Significant fibrosis
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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Created: Tue, 07 Nov 2017, 10:24:18 EST by Florian Rohart on behalf of Learning and Research Services (UQ Library)