Abstract
Genome-wide association studies have revealed that many low-penetrance cancer susceptibility loci are located throughout the genome; however, a very limited number of genes have been identified so far. Using a forward genetics approach to map such loci in a mouse skin cancer model, we previously identified strong genetic loci conferring resistance to early-stage chemically induced skin papillomas on chromosome 7 with a large number of [(FVB/N×MSM/Ms)×FVB/N] F1 backcross mice. In this report, we describe a combination of congenic mapping and allele-specific alteration analysis of the loci on chromosome 7. We used linkage analysis and congenic mouse strains to refine the location of Stmm1 (Skin tumor modifier of MSM 1) locus within a genetic interval of about 3 cM on proximal chromosome 7. In addition, we used patterns of allele-specific imbalances in tumors from F1 backcross and N10 congenic mice to narrow down further the region of Stmm1 locus to a physical distance of about 5.4 Mb. To gain the insight into the function of Stmm1 locus, we carried out a long term BrdU labelling experiments with congenic mice containing Stmm1 locus. Interestingly, we observed a decrease of BrdU-LRCs (Label Retaining Cells) in a congenic strain heterozygous or homozygous for MSM allele of Stmm1. These results suggest that Stmm1 responsible genes may have an influence on papillomagenesis in the two-stage skin carcinogenesis by regulating epidermal quiescent stem cells.
Highlights
Identification of the specific genetic variants responsible for increased susceptibility to familial or sporadic cancers remains an important but challenging goal with major implications for the prediction of individual cancer risk, as well as for improved strategies for prevention or targeted therapy [1,2,3,4]
We have recently identified a series of skin papilloma resistance loci, Stmm (Skin tumor modifier of MSM) loci, using F1 backcross mice between a wild derived inbred mouse strain (MSM) and a susceptible inbred mouse strain (FVB/N)
The location of Stmm1 was refined to a genetic interval of about 3 Chromosomal region (cM) on proximal chromosome 7 by using multiple congenic lines
Summary
Identification of the specific genetic variants responsible for increased susceptibility to familial or sporadic cancers remains an important but challenging goal with major implications for the prediction of individual cancer risk, as well as for improved strategies for prevention or targeted therapy [1,2,3,4]. For many complex-trait diseases, including cancer, low-penetrance susceptibility alleles account for a very small proportion of the total cancer risk [8], leading to considerable discussion of the best approaches to discover the majority of disease-causing alleles in human populations. For these reasons, complementary gene mapping and validation approaches including cross-species comparisons using animal models are required to identify genes that modify disease phenotypes, including the risk of developing cancer [9,10,11]. We previously reported mapping of Stmm and 2 (Skin tumor modifier of MSM), which confer resistance to skin tumor development on mouse chromosome 7 in a cross between the resistant Japanese
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