The spectra of large second-step mutations are similar for two different mouse autosomes

Loss of tumor suppressor gene expression via mutations plays a critical role in cancer development, particularly when occurring in heterozygous cells. These so-called "second-step" mutational events are often large in size and arise most often from chromosome loss, mitotic recombination, or interstitial deletion. An open question in cancer research is whether different chromosomes are equally susceptible to formation of large mutations, or alternatively if the unique sequence of each chromosome will lead to chromosome-specific mutational spectra. To address this question, the spectra of second-step mutations were determined for chromosomes 8 and 11 in Aprt and Tk mutants, respectively, isolated from primary kidney clones heterozygous for both loci. The results showed that the spectra of large mutational events were essentially the same. This observation suggests that internal and external cellular environments provide the driving force for large autosomal mutational events, and that chromosome structure per se is the substrate upon which these forces act.