Journal Article

Perturbations of the <i>Ink4a/Arf</i> gene locus in aflatoxin B<sub>1</sub>-induced mouse lung tumors

Andrew S. Tam, Theodora R. Devereux, Arti C. Patel, Julie F. Foley, Robert R. Maronpot and Thomas E. Massey

in Carcinogenesis

Volume 24, issue 1, pages 121-132
Published in print January 2003 | ISSN: 0143-3334
Published online January 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/24.1.121
Perturbations of the Ink4a/Arf gene locus in aflatoxin B1-induced mouse lung tumors

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Lung tumors from AC3F1 mice treated with aflatoxin B1 (AFB1), were examined for loss of alleles, point mutations and hypermethylation of CpG sites within the promoters of the two genes in the Ink4a/Arf gene locus. Loss of microsatellite alleles in the Ink4a/Arf region occurred in 22 of 74 (30%) AFB1-induced lung tumors. Fifty-one of 61 (83%) tumors had at least partial methylation of CpG sites within the p16Ink4a promoter-exon 1α region. At least partial methylation of CpG sites was observed in 43 of 49 (88%) tumors analyzed for p19Arf promoter hypermethylation, with methylation of identified transcription factor binding sites or consensus sequences occurring in 21 tumors (DMP1/Ets in two tumors, CTCF in four tumors, E2F in three tumors, Sp1 in 16 tumors). Two tumors contained point mutations in the p19Arf promoter. Nuclear staining for p19Arf was decreased by 80–100% in 41 of 71 (58%) tumors. The concordance between p19Arf molecular perturbations and altered protein expression was 63%. However, upon comparing p19Arf promoter perturbations (i.e. methylation of functional transcription factor binding sites and point mutations) and altered p19Arf expression, the concordance was 86%, suggesting a mechanism for changes in protein expression in some tumors. There was an absence of a mutually exclusive relationship between disruption of p53 and p19Arf, since the concordance was 62%. Similarly, no evidence was found of inverse relationships between perturbation of p16Ink4a and p19Arf (43% concordance) or p16Ink4a and p53 (37% concordance), suggesting that inactivation of these genes occurs independently and provides evidence that, although these genes may participate in cooperative cellular pathways, they also have functions in independent pathways that are important in mouse lung tumorigenesis.

Keywords: AFB1; aflatoxin B1; Cdk, cyclin-dependent kinases; CpG, cytosine-guanine dinucleotides; LOH, loss of heterozygosity; NSCLC, non-small cell lung carcinoma; RB, retinoblastoma; SSCP, single-strand conformation polymorphism

Journal Article.  10966 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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