Genetic Control of Tumour Susceptibility in Mouse Skin Carcinogenesis

The development of tumours in mouse, as in humans, is a multiple genetic process. The molecular analysis of somatic mutations in tumours has led to the association of many oncogenes and tumour suppresser genes with a particular genetic events in tumourigenesis. However, the genes that control susceptibility to tumour formation are largely unknown. To identify these tumour susceptibility genes, genetic linkage analysis was carried out using DMBA-TPA two stage mouse skin carcinogenesis system. Linkage analysis was first carried out in the FI backcross mice (FVB/N x C57BL/6J)F1 X FVB/N). At least seven loci on chromosomes 1, 4, 6, 7, 9, 10 and 12 were found to be involved in skin tumour development. Particularly, the locus D4Mit126 was associated with papilloma, while the locus D9Mit269 with both papilloma and carcinoma. Substantial contribution to tumour susceptibility also came from locus-locus interaction. The papilloma formation was influenced by the interaction of D4Mit126-D12Mit203 and D6Mit14-D9Mit269, and the carcinoma formation was affected by the interaction of D7Mit83-D10Mit134. To confirm the loci identified in the backcross analysis, a further intensive studies on (FVB/N X C57BL/6J)F2 cross was carried out. In addition to the loci on chromosomes 4, 6, 9 and 12, seven new loci on chromosomes 3, 5, 10, 11, 15 and 16 were identified to be associated with papilloma formation. Significant contributions came from loci D6Mitl4, D10Mit248 and D12Mit68, as well as the interactions of D11Mit99- D3Mit49, D10Mit248-D16Mit51 and D16Mit64-D15Mit189. The loci linked to carcinoma formation were found at loci D3Mit46, D8Mit211 and D12Nds2. The results of these two linkage studies demonstrate that the susceptibility to skin tumour development is influenced by multiple genetic loci and their interactions. The fact, that the loci identified to be associated with papilloma and carcinoma are mostly different, implies that the development of papillomas and carcinomas is under different genetic controls