Genetic Discovery Made for Familial Glioma

Truncating mutations in the POT1 gene may contribute to the development of familial glioma

medwireNews: Scientists have identified several mutations in the protection of telomeres protein 1 (POT1) Gene in patients with familial glioma, pointing to a role for telomere regulation in the disease’s aetiology.

“To our knowledge, this is the first article that identifies telomeric genes associated with glioma susceptibility”, say Melissa Bondy, from Baylor College of Medicine in Houston, Texas, USA, and co-authors in the Journal of the National Cancer Institute.

Whole exome sequencing results for 90 glioma patients from 55 families revealed that two families carried different mutations resulting in truncated POT1. Specifically, seven members of the first family carried the p.G95C mutation, three of whom had glioma. The second family had six members carrying the p.E450X mutation, two of whom had glioma.

And further POT1 analysis in 264 patients from an additional 246 families identified a third family affected by another protein-changing mutation, p.D617Efs.

Moreover, all the glioma families with POT1 mutations had at least one member with oligodendroglioma, suggesting the variants could be associated with a histologically specific susceptibility to the disease.

Examination for POT1 mutations in 6200 unselected individuals gave just one example of a truncating mutation and just 6.25% of the 64 other POT1 mutations identified were in the same protein region as those associated with glioma.

“Thus, not only are the specific mutations identified here very rare…, the mutation types themselves are uncommon across a normal population and are likely deleterious”, the researchers write.

POT1 is part of the shelterin complex, binding to tripeptidyl peptidase (TTP1) and modulating Telomerase activity, the team explains.

Germline POT1 mutations have previously only been associated with melanoma. Although none of the patients in the current study had melanoma, the researchers note that excess cases of the skin cancer have been reported in the past for families affected by glioma.

“Our results indicate that families with multiple oligodendrogliomas or multiple primary cancers (eg, melanoma and glioma) may benefit from sequenced-based screening for POT1 mutations to assess their risk and for guiding screening and surveillance plans individualized to carriers”, suggest Melissa Bondy and co-authors.

“Further studies are called for to examine the mutational status of POT1 in individuals who carry germline mutations in the gene.”


Bainbridge MN, Armstrong GN, Gramatges MM, et al. Germline mutations in shelterin complex genes are associated with familial glioma. J Natl Cancer Inst 2014; Advance online publication 7 December. doi:10.1093/jnci/dju384

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