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Quantitative Trait Loci Affecting 4-Nitroquinoline 1-oxide-induced Tongue Carcinogenesis in the Rat¹

Department of Oral Pathology, Kagoshima University Dental School, Kagoshima 890 [J-i. T., Y. H., H. M., M. K.]; Department of Pathology, Saitama Cancer Center Research Institute, Ina, Saitama 362 [J-i. T., H. S.]; and Department of Pathology and Biology of Diseases, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606 [H. H., S. H., Y. Y., T. K.], Japan

The incidence of tongue carcinomas (TCs) induced by oral administration of 4-nitroquinoline 1-oxide in rats is strain dependent. The inbred Dark-Agouti (DA) strain showed a much higher susceptibility to large mass-forming infiltrative TCs than did the Wistar-Furth (WF) strain. Our previous study (M. Kitano et al., Jpn. J. Cancer Res., 87: 1097–1101, 1996) on crosses between these two strains postulated a dominant susceptibility gene in DA and a dominant resistance gene in WF rats. The present study mapped these loci by analyzing the backcrosses to each parent with simple sequence repeat polymorphisms. Five quantitative parameters were analyzed: (a) the number of TCs > 5 mm in diameter; (b) the total number of TCs per rat; (c) the diameter of the largest TCs (DTC_max values); (d) the number of non-TC cancers per rat; and (e) and the number of cancers of any site per rat. All of these parameters were closely correlated (P < 0.0001). DA rats had a semidominant gene (Stc1) favoring the development of 4-nitroquinoline 1-oxide-induced cancers on chromosome 19, closely linked to D19Mit9. Peak linkage was observed 4 cM distal from D19Mit9, with a logarithm of the odds (lod) score of 5.72 for the number of large TCs and 6.08 for the DTC_max. On the other hand, WF rats had a semidominant gene (Rtc1) mapped between D1Mit1 and D1Mit3, 20 cM from D1Mit1, with a peak lod score of 3.30 for both the number of large TCs and the DTC_max. The main effect of Rtc1 seemed to be to reduce the size of the TCs. The action of these genes was dose dependent and cooperative. The final incidence of TC in DA, WF, F1, and backcross rats seemed to be explained by combinations of genotype at these two loci. Possible candidate genes for Stc1 and Rtc1 are discussed.

¹ Supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports and Science, Japan and a grant from the Japanese Owner's Association.

² To whom requests for reprints should be addressed, at Department of Oral Pathology, Kagoshima University Dental School, 8-35-1 Sakuragaoka, Kagoshima 890, Japan. Phone: 81-99-275-6140; Fax: 81-99-275-6148.

Received 9/16/97. Revised 2/ 9/98. Accepted 2/18/98.

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