Oral Presentation 2015 Annual Meeting of the Australasian Society for Dermatology Research

The Tgfb2/Rrp15 locus is an innate modifier of melanoma development (#7)

Blake Ferguson 1 , Ramesh ram 2 , Herlina Y Handoko 1 , Pamela Mukhopadhyay 1 , Grant Morahan 2 , Grame J Walker 1
  1. QIMR Berghofer, Herston, QLD, Australia
  2. Centre for Diabetes Research, Western Australian Institute of Medical Research, Perth, WA, Australia

Treatments for melanoma are aimed at late stage disease. It is  important to develop treatments that can strengthen a person’s ability to prevent growth of the tumor. This would be particularly useful after excision of early stage melanomas, where undetectable tumour cells can later grow to cause life-threatening disease. This should be feasible using a genetic strategy but it is difficult to determine why some high-risk individuals (e.g. with many naevi) develop melanoma, and some do not, due to large individual differences in lifestyle and in particular different interventions and treatments. We have approached this by utilizing a transgenic murine MM model crossed onto many different strain backgrounds. This was done using the Collaborative Cross (CC), a cohort of 100’s of genetically-defined strains designed to provide a means of mapping genes for complex diseases. We discovered a group of strains that develop MM very fast, and another group that develop MM very slowly or not at all (the latter were resistant because they had naturally-occurring genes that prevent melanoma). From this unbiased genetic screen we have mapped a large effect locus to a 1 Mb region of chromosome 1 containing only 5 genes, with the best candidates being Tgfb2 and Rrp15. We are utilizing the flexibility of the mouse system to reveal natural biological processes that modulate melanoma growth. SNPs in the human TGFB2/RRP15 interval have been associated with decreased survival and increased recurrence in MM patients suggesting that the locus we have mapped is relevant in human MM. Hence, while genes for pigmentation and Vitamin D metabolism, for instance, have been exposed to different evolutionary selection between mice and humans, it is not clear that this is the case for MM modifiers, which only come to light in the context of driver mutations in melanocytes (BRAF or NRAS).