title: Melanoma susceptibility as a complex trait: genetic variation controls all stages of tumor progression.
abstract: 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.
authors.affiliation: Queensland Institute of Medical Research, Herston, Queensland, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Ferguson
authors.affiliation: The Centre for Diabetes Research, Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Ram
authors.affiliation: Queensland Institute of Medical Research, Herston, Queensland, Australia.
authors.forename: H Y
authors.initials: HY
authors.lastname: Handoko
authors.affiliation: Queensland Institute of Medical Research, Herston, Queensland, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Mukhopadhyay
authors.affiliation: School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: H K
authors.initials: HK
authors.lastname: Muller
authors.affiliation: The University of Queensland, Centre for Clinical Research, Herston, Queensland, Australia.
authors.forename: H P
authors.initials: HP
authors.lastname: Soyer
authors.affiliation: The Centre for Diabetes Research, Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Morahan
authors.affiliation: Queensland Institute of Medical Research, Herston, Queensland, Australia.
authors.forename: G J
authors.initials: GJ
authors.lastname: Walker
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020412:Multifactorial Inheritance / Q000235:genetics; D009154:Mutation; D009367:Neoplasm Staging; D009506:Nevus / Q000235:genetics / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology
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