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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 volume 23, pages 3033–3039 (2004)Cite this article

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.

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Acknowledgements

This work was supported by the NIH Grant CA17613 (C Herzog). We thank Dr Basil Rigas for use of the imaging equipment and software, and Drs Frederick Tyson and Alvin Malkinson for the cell lines.

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Authors and Affiliations

  1. Institute for Cancer Prevention, Valhalla, 10595, NY, USA

    Christopher R Herzog, Nomar Bodon & Brian Pittman

  2. National Institute of Environmental Health Sciences, Research Triangle Park, 27709, NC, USA

    Robert R Maronpot & Theodora R Devereux

  3. Queen's University, Kingston, KL7 3N6, Ont., Canada

    Thomas E Massey

  4. University of Cincinnati, Cincinnati, 45267-0056, OH, USA

    Marshall W Anderson

  5. Washington University, St. Louis, 63110-1093, MO, USA

    Ming You

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  1. Christopher R Herzog
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Correspondence to Christopher R Herzog.

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Herzog, C., Bodon, N., Pittman, B. et al. Carcinogen-specific targeting of chromosome 12 for loss of heterozygosity in mouse lung adenocarcinomas: implications for chromosome instability and tumor progression. Oncogene 23, 3033–3039 (2004). https://doi.org/10.1038/sj.onc.1207431

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