Germline mutations in shelterin complex genes are associated with familial glioma

Abstract

Gliomas are the most common brain tumor, with several histological subtypes of various malignancy grade. The genetic contribution to familial glioma is not well understood. Using whole exome sequencing of 90 individuals from 55 families, we identified two families with mutations in POT1 (p.G95C, p.E450X), a member of the telomere shelterin complex, shared by both affected individuals in each family and predicted to impact DNA binding and TPP1 binding, respectively. Validation in a separate cohort of 264 individuals from 246 families identified an additional mutation in POT1 (p.D617Efs), also predicted to disrupt TPP1 binding. All families with POT1 mutations had affected members with oligodendroglioma, a specific subtype of glioma more sensitive to irradiation. These findings are important for understanding the origin of glioma and could have importance for the future diagnostics and treatment of glioma.

Figure 1.

POT1 mutations in familial glioma pedigrees. Individuals with glioma are shown as filled. Individuals with other cancers are shown as half filled. Disease and age in years at first diagnosis are given underneath the symbol, with current age or age at death (+) above it. Deceased individuals are designated with a slash through the symbol. Glioma type is shown (AnaO = anaplastic oligodendroglioma; Astro = astrocytoma; GBM = glioblastoma multiforme; Glioma = glioma unknown; Oligo = oligodendroglioma). Other cancers in the pedigree are shown (CoC = colon cancer; LC = lung cancer; Leuk = leukemia; Mel = melanoma). Mutations for all sequenced individuals are shown or listed as WT (wild-type).

Figure 2.

Germline variants identified in this study (red arrow) and associated with melanoma (blue arrow) in OB1 and OB2 regions (green) and TPP1 binding region (orange) in POT1. † indicates variant was also seen in a tumor sample. OB1/2 = Oligonucleotide binding; TPP1 = tripeptidyl peptidase I.