Oral Presentation 6th Australian Health and Medical Research Congress 2012

Mapping naevus and melanoma genes utilising the ‘Collaborative Cross’ mice (#249)

Herlina Y Handoko 1 , Ramesh Ram 2 , Blake Ferguson 1 , Grant Morahan 2 , Graeme J Walker 1
  1. Skin Carcinogenesis, Queensland Institute of Medical Research, Brisbane, QLD, Australia
  2. Centre for Diabetes Research, Western Australian Institute of Medical Research, Perth, WA, Australia

Malignant melanoma is difficult to treat. Despite recent success with BRAF inhibitors, resistance invariably develops, hence new treatments are needed. Genes are critical determinants of melanoma risk, arguably more important than sun exposure. We previously developed genetically modified mice (Cdk4R24C::Tyr-Nras) which model melanoma progression. We have combined this mouse model with the Collaborative Cross (CC), a large panel of new inbred mouse strains, as a novel approach to find genes which strongly influence melanoma development. The CC was designed to address some of the shortcomings of gene discovery using mice, such as limited genetic diversity. The CC provides a genetically-defined reference panel for the integrative analysis of complex diseases. As key strains are found, we can cross-reference with other phenotypes of those strains (e.g. other cancer susceptibility, immune responses, gene expression). We have bred our melanoma model onto the CC strains and found large differences in various melanoma-related phenotypes, including naevus and melanoma age of onset. We have mapped these phenotypes to very small chromosomal regions, containing either only one or a small number of genes, and used these data to define a molecular pathway for melanoma progression. The apparent congruence of much of our data with human melanoma genetics highlights the power of our approach. Our findings suggest that melanoma progression is controlled not only by stochastic events occurring over time, but also by different inherited factors at each stage. The discovery of genes that explain why naevi can develop so frequently, and often convert to melanoma, will lead to a much fuller understanding of melanoma progression. Especially attractive as potential therapeutic targets are protective genes that are dominant over the oncogenic mutations known to generate melanoma in both mice and humans (e.g. CDK4 and NRAS).