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Single Nucleotide Instability without Microsatellite Instability in Rat Mammary Carcinomas¹

Carcinogenesis Division [N. W., E. O., Y. H., T. S., M. N., T. U.] and Central Animal Laboratory [K. Y.], National Cancer Center Research Institute, Tokyo 104-0045; Division of Organic and Bio-organic Chemistry, Kyoritsu College of Pharmacy, Tokyo 105-8512 [N. W., M. M.]; Low Dose Radiation Risk and Carcinogenesis Research Group, National Institute of Radiological Sciences, Chiba 263-8555 [Y. S.]; Chromosome Research Unit, Faculty of Science, Hokkaido University, Hokkaido 060-0810 [M. C. Y.]; and First Department of Pathology, Nagoya-City University Medical School, Aichi 467-8601 [S. T.], Japan

Mutation frequencies (MnFs) of the lacI transgene and mutation rates (MRs) of the endogenous hprt gene were analyzed in two mammary carcinoma cell lines that we established from mammary carcinomas that had been induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in female lacI-transgenic rats. Using the lacI transgene, corrected MnF, which is the number of independent lacI mutations that occurred while 10² cells expanded into 10⁷ cells and which reflect the dynamic increase of point mutations, was measured. The corrected MnFs in the two mammary carcinoma cell lines (59 x 10^-6 and 72 x 10^-6 mutations) were significantly higher than that in the primary culture of normal mammary epithelium (4.7 x 10^-6). MRs of the hprt gene in the two mammary carcinoma cell lines (8.2 x 10^-7 and 11 x 10^-7 mutations/hprt/cell division) were also higher than the same control (1.4 x 10^-7). A:T to C:G transversion was observed at significantly higher frequencies in the two cell lines (6 of 24 and 6 of 25 for lacI; 10 of 67 and 19 of 92 for hprt) than in the control (0 of 6 for lacI; 0 of 4 for hprt). Taking advantage of the lacI transgene, high frequencies of A:T to C:G transversion (6 of 38 and 8 of 33, respectively) was also confirmed in the primary carcinomas of the two cell lines, which indicated the presence of a common abnormality in the cell lines and in the primary carcinomas. Both the established cell lines and their primary carcinomas were negative for microsatellite instability, which is known to be caused mainly by mismatch repair insufficiency and to increase point mutations, and for p53 mutations. These findings showed that the two cell lines, and possibly their primary carcinomas, had increases in the MRs of point mutations attributable to a mechanism(s) different from mismatch repair insufficiency, and we would suggest that such a state be designated as single nucleotide instability (SNI).

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