Exposure to genotoxic
carcinogens in tobacco
smoke is a major cause of
lung cancer. However, the effect this has on
DNA copy number and
genomic stability during lung
carcinogenesis is unclear. Here we used bacterial artificial chromosome array-based comparative genomic hybridization to examine the effect of NNK, a potent human lung
carcinogen present in tobacco
smoke, on the major genomic changes occurring during mouse lung adenocarcinogenesis. Observed were significantly more gross chromosomal changes in NNK-induced
tumors compared with the spontaneous
tumors. An average of 5.6 chromosomes were affected by large-scale changes in
DNA copy number per NNK-induced
tumor compared with only 2.0 in spontaneous lung
tumors (p = 0.017). Further analysis showed that gains on chromosomes 6 and 8, and losses on chromosomes 11 and 14 were more common in NNK-induced
tumors (p <or= 0.002). The changes on chromosomes 8, 11, and 14 were positively (p <or= 0.001) associated with the degree of
chromosome instability (CIN). This association was less significant for gains on chromosomes 6 and 12 (p = 0.035). In contrast, loss of distal chromosome 4 was very frequent (71%) in both NNK-induced and spontaneous
tumors, and showed no association with CIN phenotype. Each of these chromosomes contains sites of orthology with those altered in human
lung adenocarcinomas, suggesting similar roles in human
lung cancer. We next investigated the mechanism of NNK-induced CIN and found that a genotoxic metabolite of this
carcinogen causes numerous karyotypic changes in lung epithelial cells. With similar changes evident in NNK-induced
tumors, this suggests that the persistence of such damage in exposed lung epithelia may initiate CIN during lung
carcinogenesis. These results show for the first time that NNK potently induces gross chromosomal alterations in lung adenocarcinogenesis and modulates the evolutionary pathway of these
tumors through the recruitment of genes with altered
DNA copy number.