New chemically induced skin tumour susceptibility loci identified in a mouse backcross between FVB and dominant resistant PWK

Abstract

Background: A variety of skin cancer susceptibility among mouse strains has allowed identification of genes responsible for skin cancer development. Fifteen Skts loci for skin tumour susceptibility have been mapped so far by using the two-stage skin carcinogenesis model [induced by 7.12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)]. A few responsible genes have been identified using wild-derived dominant resistant Mus spretus mice, and one has been confirmed as a low penetrance cancer susceptibility gene in a variety of human cancers.

Results: In the present study, we found that wild-derived PWK mice developed no tumour by treatment with the two-stage skin carcinogenesis protocol. This phenotype is dominant resistant when crossed with the highly susceptible strain FVB. By analyzing the F1 backcross generation between PWK and FVB, we found empirical evidence of significant linkage at the new loci Skts-fp1 on chromosome 4 and suggestive linkage on chromosomes 1, 3, 11, 12 and 14 for skin tumour susceptibility. Skts-fp1 includes the Skts7 interval, which was previously mapped by a Mus spretus and NIH backcross. We also observed suggestive linkage on chromosomes 1 and 2 in the female population only, while suggestive linkage on chromosomes 14 and 15 only was observed in the male population. A significant genetic interaction was seen between markers of D11Mit339 and D16Mit14.

Conclusion: Analysis of this new cross may facilitate the identification of genes responsible for mouse skin cancer susceptibility and may reveal their biological interactions.

Figure 1

Distribution patterns of papilloma multiplicity. The number of papillomas 20 weeks after the initiation is plotted as histograms.

Figure 2

Interval mapping on chromosome 4. The QTL on chromosome 4 shows significant linkage to multiplicity of papilloma 20 weeks after the initiation. Black line indicates the linkage calculated for whole mice, right gray is for female mice, dark gray is for male mice. Genetic distances of each marker from centrosome are indicated as genetic position (cM) on the bottom.

Figure 3

Interval mapping on chromosome 1, 2, 14 and 15. Result of interval mapping on (A) chromosome 1, (B) chromosome 2, (C) chromosome 14 and (D) chromosome 15 are shown. Right gray line indicates the linkage for female mice and dark gray line for male mice. Genetic distances of each marker from centrosome are indicated as the genetic position (cM) on the bottom.

Figure 4

Allelic interaction between D11Mit339 and D16Mit14. Association between D11Mit339 genotype and multiplicity of papilloma 20 weeks after the initiation is shown. Black square indicates the mice with FF genotype at the D16Mit14 locus. White square indicates the mice with FP genotype at the D16Mit14 locus. Data are shown as mean ± SEM.

Figure 5

Interval mapping on chromosome 11. (A) Interval mapping results on chromosome 11 are shown for the mice with FF genotype (dark gray line) and the mice with FP genotype (right gray line) at the D16Mit14 locus. Black line indicates interval mapping for whole mice. Significant linkage is observed only in the mice with FF genotype at the D16Mit14 locus. (B) Interval mapping results on chromosome 16 are shown for the mice with FF genotype (dark gray line) and the mice with FP genotype (right gray line) at the D11Mit339 locus. Black line indicates interval mapping for whole mice. Significant linkage is observed only in the mice with FF genotype at the D11Mit339 locus. Genetic distances of each marker from centrosome are indicated as the genetic position (cM) on the bottom.