Medical College of Wisconsin
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Carcinogen-specific targeting of chromosome 12 for loss of heterozygosity in mouse lung adenocarcinomas: implications for chromosome instability and tumor progression. Oncogene 2004 Apr 15;23(17):3033-9

Date

02/03/2004

Pubmed ID

14755239

DOI

10.1038/sj.onc.1207431

Scopus ID

2-s2.0-2442490689   17 Citations

Abstract

Genotoxic carcinogens exert their tumorigenic effects in part by inducing genomic instability. We recently showed that loss of heterozygosity (LOH) on chromosome 12 associates significantly with the induction of chromosome instability (CIN) by the likely human lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and vinyl carbamate (VC) during mouse lung carcinogenesis. Here, we demonstrate the carcinogen specificity of this event and its effect on lung tumor evolution. LOH on chromosome 12 was observed in 45% of NNK-induced, 59% of VC-induced, 58% of aflatoxin B1 (AFB1)-induced, 14% of N-ethyl-N-nitrosourea (ENU)-induced and 12% of spontaneous lung adenocarcinomas. The frequency of LOH in each of the carcinogen-induced groups, except ENU, was significantly higher than in the spontaneous group (P<0.001). Deletion mapping revealed four potential candidate regions of 1-4 centiMorgans suspected to contain targeted tumor suppressor genes, with at least one expected to have a role in CIN. The relationship between LOH on chromosome 12 and additional chromosomal alterations occurring during lung tumor progression was also examined. LOH on chromosomes 1 and 14 were moderately frequent during malignant progression in tumors from all treatment groups, occurring in 21-35 and 18-33% of tumors. However, these alterations showed significant concurrence with LOH on chromosome 12 in VC-, NNK- and AFB1-induced tumors (P<0.05). The results suggest that a carcinogen-selective mechanism of lung cancer induction involves the frequent inactivation of genes on chromosome 12, including a stability gene that evidently promotes the evolutionary selection of additional chromosomal alterations during malignant progression.

Author List

Herzog CR, Bodon N, Pittman B, Maronpot RR, Massey TE, Anderson MW, You M, Devereux TR



MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Animals
Carcinogens
Chromosomal Instability
Chromosome Deletion
Chromosome Mapping
Crosses, Genetic
Ethylnitrosourea
Loss of Heterozygosity
Lung
Lung Neoplasms
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Urethane