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Recurrent allelic deletions at mouse chromosomes 4 and 14 in Myc-induced liver tumors

Oncogene volume 21, pages 1518–1526 (2002)Cite this article

Abstract

Transgenic mice expressing the c-Myc oncogene driven by woodchuck hepatitis virus (WHV) regulatory sequences develop hepatocellular carcinoma with a high frequency. To investigate genetic lesions that cooperate with Myc in liver carcinogenesis, we conducted a genome-wide scan for loss of heterozygosity (LOH) and mutational analysis of β-catenin in 37 hepatocellular adenomas and carcinomas from C57BL/6 x castaneus F1 transgenic mice. In a subset of these tumors, chromosome imbalances were examined by comparative genomic hybridization (CGH). Allelotyping with 99 microsatellite markers spanning all autosomes revealed allelic imbalances at one or more chromosomes in 83.8% of cases. The overall fractional allelic loss was rather low, with a mean index of 0.066. However, significant LOH rates involved chromosomes 4 (21.6% of tumors), 14, 9 and 1 (11 to 16%). Interstitial LOH on chromosome 4 was mapped at band C4–C7 that contains the INK4a/ARF and INK4b loci, and on chromosome 14 at band B–D including the RB locus. In man, the homologous chromosomal regions 9p21, 13q14 and 8p21–23 are frequently deleted in liver cancer. LOH at chromosomes 1 and 14, and β-catenin mutations (12.5% of cases) were seen only in HCCs. All tumors examined were found to be aneuploid. CGH analysis of 10 representative cases revealed recurrent gains at chromosomes 16 and 19, but losses or deletions involving mostly chromosomes 4 and 14 generally prevailed over gains. Thus, Myc activation in the liver might select for inactivation of tumor suppressor genes on regions of chromosomes 4 and 14 in a context of low genomic instability. Myc transgenic mice provide a useful model for better defining crosstalks between oncogene and tumor suppressor pathways in liver tumorigenesis.

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Acknowledgements

We thank Danny Rouillard for assistance with flow cytometry and Martine Lombard for technical assistance in cytogenetic preparations. This work was supported in part by grants from the Association pour la Recherche sur le Cancer (ARC contract 5236) and from the Association Franco-Chinoise pour la Recherche Scientifique et Technique (Y Wu).

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Authors and Affiliations

  1. Unité de Recombinaison et Expression Génétique (Inserm U163), Institut Pasteur, 28 rue du Dr. Roux, Paris, 75015, France

    Yuanfei Wu, Claire-Angélique Renard, Pierre Tiollais & Marie Annick Buendia

  2. Unité d'Histopathologie, Institut Pasteur, 28 rue du Dr. Roux, Paris, 75015, France

    Michel Huerre

  3. CNRS UMR 147, Institut Curie, 26 rue d'Ulm, Paris, France

    Françoise Apiou & Bernard Dutrillaux

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  1. Yuanfei Wu
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  2. Claire-Angélique Renard
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Correspondence to Marie Annick Buendia.

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Wu, Y., Renard, CA., Apiou, F. et al. Recurrent allelic deletions at mouse chromosomes 4 and 14 in Myc-induced liver tumors. Oncogene 21, 1518–1526 (2002). https://doi.org/10.1038/sj.onc.1205208

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