Susceptibility to most common cancers is likely to involve interaction between 
multiple low risk genetic variants. Although there has been great progress in 
identifying such variants, their effect on phenotype and the mechanisms by which 
they contribute to disease remain largely unknown. We have developed a mouse 
melanoma model harboring two mutant oncogenes implicated in human melanoma, 
CDK4(R24C) and NRAS(Q61K). In these mice, tumors arise from benign precursor 
lesions that are a recognized strong risk factor for this neoplasm in humans. To 
define molecular events involved in the pathway to melanoma, we have for the 
first time applied the Collaborative Cross (CC) to cancer research. The CC is a 
powerful resource designed to expedite discovery of genes for complex traits. We 
characterized melanoma genesis in more than 50 CC strains and observed 
tremendous variation in all traits, including nevus and melanoma age of onset 
and multiplicity, anatomical site predilection, time for conversion of nevi to 
melanoma and metastases. Intriguingly, neonatal ultraviolet radiation exposure 
exacerbated nevus and melanoma formation in most, but not all CC strain 
backgrounds, suggesting that genetic variation within the CC will help explain 
individual sensitivity to sun exposure, the major environmental skin carcinogen. 
As genetic variation brings about dramatic phenotypic diversity in a single 
mouse model, melanoma-related endophenotype comparisons provide us with 
information about mechanisms of carcinogenesis, such as whether melanoma 
incidence is dependent upon the density of pre-existing nevus cells. Mouse 
models have been used to examine the functional role of gene mutations in 
tumorigenesis. This work represents their next phase of development to study how 
biological variation greatly influences lesion onset and aggressiveness even in 
the setting of known somatic driver mutations.