A Specific Mutation Links Some Forms of Inherited Melanoma

A mutation that inactivates the POT1 (protection of telomeres 1) gene has been linked to the development of an inherited form of melanoma.

The POT1 gene encodes for synthesis of "protection of telomeres protein 1" protein, a nuclear protein involved in telomere maintenance. This protein functions as a member of a multiprotein complex that binds to the TTAGGG repeats of telomeres, regulating telomere length and protecting chromosome ends from illegitimate recombination, catastrophic chromosome instability, and abnormal chromosome segregation.

Investigators at the Wellcome Trust Sanger Institute (Hinxton, United Kingdom) and the University of Leeds (United Kingdom) searched for unrecognized promelanoma genes by sequencing the DNA from184 melanoma patients from 105 families recruited in the United Kingdom, The Netherlands, and Australia that were negative for variants in genes known to be linked to predisposition for developing melanoma.

They identified families where melanoma co-segregated with loss-of-function variants in the POT1gene, with a proportion of family members presenting with an early age of onset and multiple primary tumors. They showed that these variants either affected POT1 mRNA splicing or altered key residues in the highly conserved oligonucleotide/oligosaccharide-binding domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.

"Genomics is on the verge of transforming the healthcare system – this study highlights the potential clinical benefits that can be gained through genomic studies and offers potential strategies to improve patient care and disease management," said senior author Dr. David Adams, leader of the experimental cancer genetics program at the Wellcome Trust Sanger Institute. "With this discovery we should be able to determine who in a family is at risk, and in turn, who should be regularly screened for early detection."

The article linking POT1 mutations to melanoma was published in the March 30, 2014, online edition of the journal Nature Genetics.

Related Links:
Wellcome Trust Sanger Institute
University of Leeds