Genetic Mutations Predispose to Familial Melanoma

New high-risk cancer-causing mutation identified for melanoma development

Researchers have discovered that people with mutations in a POT1 (protection of telomeres 1) gene were extremely likely to develop a hereditary form of melanoma. About 1 in 20 patients with melanoma have a strong family history of the disease. In these patients, pinpointing the genetic mutations that drive disease development allows to identify those who should be part of melanoma surveillance programmes.

Currently known genetic mutations account for approximately 40% of all occurrences of inherited forms of melanoma. Basically, deleterious germline variants in CDKN2A account for most of these familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease.

Search in families negative for variants in known predisposition genes

In the current analysis, the study team set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes.

They identified families where melanoma cosegregates with loss-of-function variants in the POT1 gene, with a proportion of family members presenting with an early age of onset and multiple primary tumours.

These variants either affect POT1 mRNA splicing or alter key residues in the highly conserved 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.

The team also found that there were cases of other cancer types in families with these hereditary mutations such as leukaemias and brain tumours. It seems that mutations that deactivate the POT1 gene may underlie other cancers, not just melanoma.

The team is currently working on developing cells and mice with an inactive POT1 gene. These will be used to test potential drug therapies that alter telomere metabolism.

The first author of the study is Carla Daniela Robles-Espinoza of the Experimental Cancer Genetics, Wellcome Trust Sanger Institute, UK.

The study findings are published online on 30 March 2014 in the Nature Genetics.


Robles-Espinoza CD, Harland M, Ramsay A, et al. POT1 loss-of-function variants predispose to familial melanoma. Nature Genetics 2014; Advanced online publication 30 March. DOI: 10.1038/ng.2947

The authors declare no competing financial interests.