Gastroenterology

Gastroenterology

Volume 120, Issue 7, June 2001, Pages 1763-1773
Gastroenterology

Liver, Pancreas, and Biliary Tract
Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis*,**

https://doi.org/10.1053/gast.2001.24798Get rights and content

Abstract

Background & Aims: To evaluate how characterization of genetic alterations can help in the elucidation of liver carcinogenesis pathways, 137 tumors were analyzed. Methods: High-density allelotype, p53, Axin1, and β-catenin gene mutations were determined. Alterations were analyzed according to clinical parameters. Results: Tumors could be divided into 2 groups according to chromosome stability status. In the first group, demonstrating a chromosome stability, β-catenin mutation associated with chromosome 8p losses were frequently found as the single genetic alterations. β-catenin mutations were associated with large tumor size and with negative hepatitis B virus status. In the second group, demonstrating a chromosome instability, the most frequent allelic losses were on chromosome 1p, 4q, 6q, 9p, 13q, 16p, 16q, and 17p; Axin1 and p53 were frequently mutated. All of these alterations, except losses on 6q and 9p, were associated with hepatitis B virus infection. P53 mutations, 17p, 13q losses, and a high value of the fractional allelic loss index were associated with poor differentiated tumors, independently of risk factors. Finally, in the whole series, chromosome 9p and 6q losses were associated with poor prognosis. Conclusions: Two main pathways defined by genetic alterations show different risk factors and clinical characteristics. Furthermore, loss of chromosome 9p or 6q is an independent prognostic indicator.

GASTROENTEROLOGY 2001;120:1763-1773

Section snippets

Patients and samples

Primary hepatocellular carcinoma and matched nontumor liver tissues were obtained from 137 patients during hepatectomy (n = 109), liver transplantation (n = 26), or at autopsy (n = 2) in 4 French surgical departments from 1992 to 1998. Fibrolamellar carcinomas were excluded from the series. Tumor tissue samples were dissected and nontumor tissues (>50 mg) were taken as far from the tumor as possible. Tissues were stored at −80°C until DNA extraction using the Qiaquick extraction kit (Qiagen,

Allelotyping results

A total of 335 microsatellite markers distributed among the 39 autosomal chromosome arms were characterized for each tumor and matched nontumor DNAs. More than 70% of the loci were informative per individual, and the status of more than 99.5% of the chromosome arms have been defined as conserved or deleted in the tumor. To avoid artifactual results, for all cases, the LOH status of a chromosome arm was attributed if at least 2 adjacent markers showed LOH. In all cases, more than 99% of the

Discussion

This study provides an exhaustive analysis of the relations that exist between the genetic alterations frequently found in HCC and the histoclinical characteristics of the tumors. For the first time, search for LOH on all chromosome arms and for mutations in 3 genes, P53, β-catenin, and Axin1, were carried out on the same series of tumors. Because the previously published series have investigated only a specific subset of genetic alterations, the correlations existing between all the different

Acknowledgements

The authors thank Dr. Leigh Pascoe for helpful discussions and critical reading of the manuscript; Prof. Jean-François Flejou, Prof. Frédérique Capron, and Prof. Balabaud for providing tumor samples; Jean-Christophe Beaudoin, Damien Gerald, Christelle Vaury, Catherine Massart, Richard Hamelin, and Jan Bayer for help in the LOH, mutation, and flow cytometry screening; Jean-Michel Pawlotsky for providing HBV reference serum; and Gavin Sherlock for his kind gift of cluster software for the

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  • Cited by (0)

    *

    Address requests for reprints to: Jessica Zucman, M.D., Ph.D., INSERM U434, Laboratoire de Génétique des tumeurs, Centre d'étude du polymorphisme humain, 27 rue Juliette Dodu, 75010 Paris, France. e-mail: [email protected]; fax: (33) 15-372-5158.

    **

    Supported by the Association de la Recherche sur le Cancer (grant no. 9382), the Ligue départementale de Lutte Contre le Cancer de la Dordogne, and the INSERM.

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