Five Quantitative Trait Loci Affecting 4‐Nitroquinoline 1‐Oxide‐induced Tongue Cancer in the Rat

Abstract

In our previous study, Dark-Agouti (DA) rats were found to be highly susceptible to 4-nitroquinoline 1-oxide (4NQO)-induced tongue carcinoma (TC), whereas Wistar/Furth (WF) rats were barely susceptible. Interval mapping analysis of reciprocal backcross rats showed two quantitative trait loci (QTL) on rat chromosomes (RNO) 1 and 19. In the present study, a composite interval mapping analysis was applied to 4NQO-induced TC in 130 (DA × × × ×WF) F2 rats, demonstrating five independent QTL, Tongue squamous cell carcinoma 1-5 (Tscc1-5), responsible for phenotypic differences in the size and number of TCs in the two strains. Two of these QTL were mapped on RNO1, and the others were mapped on RNO4, 14, and 19. The DA allele at these loci consistently yielded semidominant susceptibility to TC. Out of the five loci detected in this F2 generation, Tscc1 and 2 were identical to Stc1 and Rtc1 described in our previous study, but the other three were novel. We propose a new nomenclature consistent with their function. Genome-wide screening of the F2 progeny also suggested the presence of three additional QTL on RNO5, 6, and 10. The possible roles of these loci in tongue carcinogenesis are discussed. Key words: Genetic susceptibility -QTL -Tongue cancer -Rat -4-Nitroquinoline 1-oxideTongue carcinoma (TC) is one of the most frequent malignancies in the head and neck region. An increase in TC has been reported in the Western world over the past ten years. TC has a poor prognosis because therapeutic strategies provide limited effects.1-4) For effective prevention of TC, it would be necessary to identify the genetically predisposed risk group. However, virtually nothing is known about the genetic predisposition to TC.Recently, we found that the Dark-Agouti (DA) strain of rats had an extremely high susceptibility to 4-nitroquinoline 1-oxide (4NQO)-induced squamous cell carcinoma of the tongue. Virtually 100% of DA rats given drinking water containing 0.001% 4NQO developed one or more large TC within 180 days of administration, whereas the Wistar/Furth (WF) strain of rats was much less susceptible. [5][6][7][8] In the previous study with reciprocal backcrosses between DA and WF rats, 7,8) DA rats were shown to have a semidominant susceptibility locus, Stc1 (Susceptibility to TC-1) on rat chromosome (RNO) 19, and WF rats, another semidominant resistance gene Rtc1 (Resistance to TC-1) on RNO1.In this study, to scrutinize further the genetic predisposition to TC in the rat, we studied F2 progeny between DA and WF strains by means of a composite interval mapping analysis. After several statistical trials, we employed a quantitative parameter for tumor number, TC >3 mm in diameter, rather than TC >5 mm. In addition to two quantitative trait loci (QTL) described in the previous study, three novel QTL have been found to affect TC susceptibility. These five QTL explain almost all phenotypic variations between the two strains. MATERIALS AND METHODS Animals and phenotypeThe origin of DA rats is related to Copenhagen rats, although there is n...

Oral Cavity and Esophageal Carcinogenesis Modeled in Carcinogen-Treated Mice

“…4-NQO also can undergo redox cycling to produce reactive oxygen species that result in mutations and DNA strand breaks (16,17). 4-NQO has been shown to induce oral cavity SCCs in rats (18) and mice (11,19,20). In the rat, the 4-NQO model has been used to test cancer chemopreventive agents (21)(22)(23)(24)(25).…”

“…In the rat, the 4-NQO model has been used to test cancer chemopreventive agents (21)(22)(23)(24)(25). 4-NQO treatment has generally been performed by two different methods, either painting 4-NQO on mouse tongues, using a dose of 5 mg/ml (11,19), or dissolving 4-NQO in the drinking water for rats (18,26). Administration of 4-NQO produces a temporal carcinogenesis progression model that demonstrates multiple dysplastic, preneoplastic, and neoplastic lesions after long-term treatment (11).…”

Oral Cavity Carcinogenesis Modeled in Carcinogen-Treated Mice

“…Generally, there were two different methods of 4NQO treatment. One was to paint 4NQO on tongues 8,12) , the other one was to dissolve it in the drinking water for rats 5,12) . And the results showed 4NQO was a better carcinogen for the production of oral carcinogenesis compared to DMBA in rat model 13) .…”

“…4-Nitroquinoline-1-oxide (4NQO), a synthetic water soluble carcinogen, had been confirmed can induce OSCCs in rats 5) and mice [6][7][8] . Generally, there were two different methods of 4NQO treatment.…”

“…Previously, several animal models for OSCC development were established, including hamster, rat, and mouse models [3][4][5][6][7][8][9][10][11] .…”