Whole-genome sequencing of melanoma reveals frequent PREX2 mutations
The rates of genetic mutations rose along with chronic sun exposure
- Date : 11 May 2012
- Topic : Melanoma
A research team led by scientists from the Broad Institute and Dana-Farber Cancer Institute has sequenced the whole genomes of 25 metastatic melanoma, confirming the role of chronic sun exposure and revealing new genetic changes important in tumour formation.
In an article published online May 9 in Nature, the authors provide the first high-resolution view of the genomic landscape of human melanoma. Previous genetic analyses have focused on the exomes of many types of cancers, concentrating on the tiny fraction of the genome that provides the genetic code for producing proteins. Whole genomes contain a wealth of genetic information, and by sequencing and analysing metastatic melanoma scientists can learn vastly more about the variety of genetic alterations that matter in melanoma.
When the scientists explored the whole genome data generated and analysed, they found that the rates of genetic mutations rose along with chronic sun exposure in patients, confirming the role of sun damage in disease development.
Whole-genome analysis of human melanoma shows for the first time the existence of many structural rearrangements in this tumour type
As expected, the scientists detected known BRAF and NRAS mutations in 24 of the 25 tumours. One other gene leaped out: PREX2, previously implicated in breast cancer for blocking a tumour-suppressor pathway, was altered in 44% of patients. In a larger validation cohort of 107 tumours, the frequency of the mutation was 14%.
PREX2 is mutated in a convergence of genetic disruption that appears to accelerate tumour development. Its mutations occurred not just at hot spots that typically turn on an oncogene. The alterations were also scattered across the length of the gene in a pattern typically seen when tumour suppressors are turned off.
When PREX2 functions normally, it interacts with PTEN, a well known as a tumour suppressor involved in controlling growth in normal cells. Mouse experiments in lab at Dana-Farber showed that PREX2 mutations spurred tumour growth in ways that are not fully understood.
According to study researchers PREX2 may be a very interesting new category of mutated cancer genes that point to at least one and maybe more pathways that would be worth targeting therapeutically in melanoma.
The researchers concluded that new melanoma genes remain to be discovered by this unbiased approach, as illustrated by the discovery of PREX2 and the demonstration of its oncogenicity in vivo.
The work was supported by the USA National Human Genome Research Institute, National Cancer Institute, FWF-Austrian Science Fund, NIH Director's New Innovator Award, and the Burroughs-Wellcome Fund.
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