Germline Variants in Centromere Binding Protein 126 Predispose to Glioblastoma

Area of Science:

• Genomics
• Cancer Genetics
• Neuro-oncology

Background:

• Glioblastoma (GBM) is the most common primary malignant brain tumor in adults.
• Familial GBM, though rare (5%), often has an unresolved genetic basis, suggesting undiscovered susceptibility genes.
• Studying familial clusters can reveal rare inherited variants with significant biological impact on gliomagenesis.

Purpose of the Study:

• To investigate the genetic underpinnings of familial glioblastoma (GBM) in a multi-generational family.
• To identify shared rare germline variants associated with GBM susceptibility.
• To functionally validate candidate genes involved in gliomagenesis.

Main Methods:

• Whole-genome sequencing was performed on three affected family members (proband and two relatives) and their tumor samples.
• Rare coding variants shared among the family members were identified.
• Candidate genes were functionally interrogated using pooled loss-of-function CRISPR screens in neural progenitor cells (NPCs) and xenograft models.

Main Results:

• 139 candidate genes harboring rare coding variants were identified.
• Functional screens highlighted Centrosomal Protein of 126 kDa (CEP126) as a top hit.
• Disruption of CEP126 significantly enhanced survival and tumorigenicity in neural progenitor cells.

Conclusions:

• The study establishes a framework for investigating rare germline cancer predisposition variants.
• CEP126 is identified as a novel, biologically relevant gene predisposing to glioblastoma.
• Further research into CEP126 is warranted for mechanistic understanding and clinical validation in GBM.