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.

Recent developments in brain tumor predisposing syndromes

“…The penetrance of the mutations was incomplete with roughly one third of the carriers developing gliomas. The majority of the tumors were of oligodendrocytic rather than astrocytic origin [128]. It should be noted that this study was based on a low number of patients, and additional studies are required to fully understand the role of POT1 as a glioma predisposition gene.…”

“…Interestingly, two of the melanoma predisposing mutations (Tyr89Cys) and (Gln94Glu) were within six residues from one of the GLIOGENE mutations (Gly95Cys). One case of an undisclosed type of brain tumor occurred in the Tyr89Cys melanoma family [129], but no cases of melanoma were reported in the Gly95Cys GLIOGENE family [128]. In contrast, in colorectal cells increased levels of POT1 were seen in tumor tissues compared to adjacent normal tissues, and the relative telomere length was increased in proportion to the POT1 level [130].…”

“…Recently, the protection of telomerase protein 1 (POT1) was identified as a novel glioma causing gene by exome sequencing in families with at least two blood samples available by the GLIOGENE biobank [128]. The study identified three different germline mutations in three independent families with familial gliomas.…”

“…It should be noted that this study was based on a low number of patients, and additional studies are required to fully understand the role of POT1 as a glioma predisposition gene. Conversely, mutations in this region of POT1 were extremely rare in the general population (4/6000 individuals), further promoting the idea that POT1 is a novel gene predisposing the carriers to development of gliomas [128].…”

Comparative oncology: what dogs and other species can teach us about humans with cancer

“…Human patients often present with neurological symptoms such as headaches and seizures, and despite the vast amount of genomic data and novel therapies now available, GBMs recur quickly and aggressively after resection and often lead to death [124]. Several of the human cancer predisposition syndromes include gliomas in their clinical spectrum [127][128][129][130][131][132][133], supporting the genetic risk for development of these tumours.…”