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Genetic mechanisms involving ultraviolet light in the development of cutaneous malignant melanoma

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Improved mutation screening for malignant melanoma

Cutaneous malignant melanoma causes the greatest number of deaths from skin cancer, worldwide. A team of scientists with a European project have identified and defined gene mutations associated with this cancer using a novel mutation analysis protocol.

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Cutaneous malignant melanoma (CMM) is the result of the transformation of normal melanocytes into melanoma cells, by melanomagenesis. Recent data suggest multiple pathways involved in melanoma pathogenesis with a progression of mutations that alter cell proliferation and differentiation. Members of the European funded project MAUVE investigated the types of mutation prevalent in the development of CMM. As CMM development hinges on the stepwise progression of mutation induced cell changes, an integral part of this research was the development of a new analysis for changes in DNA. The basis for this development was the combination of two protocols that resulted in a highly efficient screening tool. The first of these methods was single stranded conformation polymorphism (SSCP) analysis capable of detecting DNA polymorphisms and mutations. This was merged with denaturing gradient gel electrophoresis (DGGE) that screens small fragments of DNA specifically for point mutations. The team went on to analyse mutations linked with different stages and forms of melanoma development. The N-ras and BRAF oncogenes provided a very good example of association with specific cell stages and types. The gene known as N-ras functions as a biomolecular switch and is often deregulated in tumour cells so this can lead to invasion, metastasis and reduced programmed cell death or apoptosis. The scientists found that N-ras mutations were associated with congenital naevi. By contrast, mutations in BRAF genes which are frequently associated with cancers including malignant melanoma are more often found in conjunction with dysplastic naevi. Dysplastic naevi are considered to occupy a developmental middle ground between the benign melanocyte and CMM. Further work on tumour suppressor gene and cell division cycle inhibitor mutations added to the evidence that melanoma development was largely linked to specific identifiable mutations. Significantly, these can be induced by exposure to UV-A and UV-B radiation. Early detection of cutaneous melanoma is the best way to reduce mortality. This form of cancer is highly aggressive even in the early stages so prompt diagnosis is crucial. The potential markers identified in this piece of research could be instrumental in improved characterisation of cells from melanoma biopsies.

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