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

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 beta-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 beta-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.

journal_name

Oncogene

journal_title

Oncogene

authors

Wu Y,Renard CA,Apiou F,Huerre M,Tiollais P,Dutrillaux B,Buendia MA

doi

10.1038/sj.onc.1205208

subject

Has Abstract

pub_date

2002-02-28 00:00:00

pages

1518-26

issue

10

eissn

0950-9232

issn

1476-5594

journal_volume

21

pub_type

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