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| Skin, hair, eye colour and cancer – MC1R/OCA2, the genetic links |
| | Pigmentary traits such as red hair and fair skin, moles, eye colour, lack of tanning ability and propensity to freckle have been identified as genetic risk factors for skin cancer when combined with the environmental risk factor of high ultraviolet exposure.
The major areas of investigation are the role of the OCA2 gene in directing eye colour, and the role of human melanocortin-1 receptor (MC1R) gene variants in directing skin phototype and response to UV-induced ligand binding and receptor activation.
The MC1R coding sequence is highly polymorphic in human populations and we have examined MC1R variant allele frequencies in the general community as well as a collection of adolescent dizygotic and monozygotic twins with defined pigmentation characteristics.
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Variant allele frequencies have also been determined in several case-control studies of sporadic melanoma, basal cell carcinoma and squamous cell carcinoma, and in familial melanoma kindreds collected within Australia.
These studies have shown that three MC1R alleles – Arg151Cys, Arg160Trp and Asp294His – were associated with increased risk in all forms of skin cancer and with penetrance and age of onset in familial melanoma in CDKN2A mutation carriers.
There is a significant MC1R variant allele heterozygote carrier effect on skin phototype and skin cancer risk, which indicates that these alleles do not behave in a strictly recessive manner.
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| Characterisation of melanoblast stem cell differentiation |
| | The process of development and differentiation of the melanocytic cell lineage is being investigated using primary melanoblast and melanocyte cells cultured in vitro from human skin.
This will provide information to allow the genes and processes involved in melanoma tumour formation and metastasis to be examined.
These studies focus on the identification and molecular characterisation of the genes involved in melanocyte function.
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| Mechanisms of melanoma metastasis |
| | Expression of the ß3 integrin gene in melanoma in situ has been found to be the single most important marker of metastasis yet discovered.
Experiments to investigate the effects of this expression has involved the use of Adenoviral gene transduction of the â3 integrin subunit into radial growth phase (RGP) melanoma cell lines and differential gene screening.
A skin reconstruction model was used to assay the invasivness of RGP melanoma cells after ectopic â3 integrin expression and these studies have discovered induction of the anti-adhesive protein osteonectin is required for melanoma metastasis. |
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