Melanoma susceptibility as a complex trait: genetic variation controls all stages of tumor progression

Ferguson B., Ram R., Handoko H.Y., Mukhopadhyay P., Muller H.K., Soyer H.P., Morahan G. and Walker G.J. (2014) Melanoma susceptibility as a complex trait: genetic variation controls all stages of tumor progression. Oncogene, 34 22: 2879-2886. doi:10.1038/onc.2014.227


Author Ferguson B.
Ram R.
Handoko H.Y.
Mukhopadhyay P.
Muller H.K.
Soyer H.P.
Morahan G.
Walker G.J.
Title Melanoma susceptibility as a complex trait: genetic variation controls all stages of tumor progression
Journal name Oncogene   Check publisher's open access policy
ISSN 0950-9232
1476-5594
Publication date 2014-08-04
Year available 2015
Sub-type Article (original research)
DOI 10.1038/onc.2014.227
Open Access Status Not yet assessed
Volume 34
Issue 22
Start page 2879
End page 2886
Total pages 8
Place of publication London, England, U.K.
Publisher Nature Publishing Group
Language eng
Subject 1311 Genetics
1306 Cancer Research
1312 Molecular Biology
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.
Keyword Biochemistry & Molecular Biology
Oncology
Cell Biology
Genetics & Heredity
Biochemistry & Molecular Biology
Oncology
Cell Biology
Genetics & Heredity
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID DP11010206
1037321
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Medicine Publications
 
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Created: Wed, 01 Apr 2015, 08:20:10 EST by Matthew Lamb on behalf of School of Medicine