by ecancer reporter Clare Sansom

Melanoma, which arises in melanocytes, the cells that produce the dark pigment melanin, is the most deadly form of skin cancer.

The most important risk factor for its development is prolonged exposure to ultra-violet (UV) radiation from the sun, often in early life.

It is a genetically complex disease, and mutations in a number of genes have already been associated with greater or lesser increases in the risk of melanoma development.

A large group of researchers led by Levi Garraway of the Dana-Farber Cancer Institute and Michael Berger of the Broad Institute of Harvard and MIT, both based in Cambridge, Massachusetts, USA, has now conducted a comprehensive investigation of the genetic aberrations associated with melanoma development.

Garraway, Berger and their co-workers sequenced the genomes of 25 metastatic melanomas and of blood samples taken from the same individuals. All melanomas sequenced were metastases from primary tumours of different subtypes and arising on different parts of the skin. One sample came from a patient with a clinical history of chronic UV exposure.

The tumour samples were found to have an average mutation rate of 30 somatic mutations per megabase of DNA, but this figure masked a large difference of almost two orders of magnitude between samples.

The highest mutation rate was found in the sample from the patient with chronic UV exposure, the next highest rates in melanomas that had developed on the trunk, and lower rates still in those that had developed on hairless skin of the extremities and had been classified as the acral subtype. The most common type of mutation was the C à T transition, with 93% of substitutions in the tumour with the highest mutation rate being of this type.

Eleven genes were found to be mutated at significant rates in the 25 tumour samples. Not unexpectedly, the two most significantly mutated genes were the oncogenes NRAS and BRAF. However, a third highly significant gene, PREX2, had only been previously associated with solid tumour development in a few reports.

This gene encodes a phosphatidy-linositol 3,4,5-trisphosphate RAC exchange factor that is known to interact with and modulate the function of the tumour suppressor PTEN.  Eleven of the 25 melanomas had at least one non-synonymous mutation in PREX2, and nine had rearrangements close to this gene. 

The researchers then validated their finding by sequencing the PREX2 region in a total of 107 further paired samples of melanoma and normal tissue. They identified 15 non-synonymous mutations in this cohort, representing a mutation rate of 14%. They then explored the function of the PREX2 protein in melanoma development by expressing PREX2 containing six representative mutations in human melanocytes also engineered to express mutated NRAS, and transplanting these cells into immunodeficient mice.

Mice transplanted with cells expressing three truncated PREX2 variants and one point mutation developed tumours more quickly than control mice. These results suggested that PREX2 acts as an oncogene in melanoma. However, the pattern of mutations observed, with point mutations and truncations scattered over all functionally annotated domains of the protein, was distinct from that found in “classic” oncogenes.

Garraway, Berger and their colleagues suggested that the oncogenic mutations in the PREX2 gene might lead to over- or aberrant expression of the gene product and to tumour promotion through subtle interactions with protein interaction partners such as PTEN. Although it is unlikely that PREX2 itself will prove to be a good drug target, its discovery should help scientists probe the pathways through which this potentially devastating disease develops.

Reference

Berger, M.F., Hodis, E., Heffernan, T.P. and 45 others (2012). Melanoma genome sequencing reveals frequent PREX2 mutations. Nature, published online ahead of print 10 May 2012. doi:10.1038/nature11071