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.