Germline Variants in Centromere Binding Protein 126 Predispose to Glioblastoma

Loss of function of CEP126 (centrosomal protein of 126 kDa) conferring a survival and tumorigenic advantage to neural progenitor cells.

Only 5% of glioblastomas arise in a familial context, and the genetic basis of these forms remains unresolved in most affected clusters. The authors studied a family with glioblastoma clustering across two generations, performing whole-genome sequencing on available blood and tumour samples from the proband and two confirmed affected relatives. Rare coding variants shared by all three participants were identified in 139 candidate genes; pooled loss-of-function CRISPR screens in human neural progenitor cells, in vitro and in heterotopic xenograft models, identified CEP126 as the top hit. Disruption of CEP126 conferred a survival and tumorigenic advantage on neural progenitor cells. The authors propose CEP126 as a glioblastoma predisposition gene, pending mechanistic and genetic validation.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The strategy — rare variants shared within a family, then CRISPR screening to prioritise 139 candidates — is elegant and transferable to other unexplained tumour clusters. But the genetic evidence rests on a single family, and the screen tests gene-level loss of function rather than the effect of the variant itself: nothing yet justifies reporting CEP126 diagnostically or offering familial screening. To be filed as a promising candidate, pending independent families.

Analysis by Dr Thibaut Benquey