The Impact of CDKN2A Deletion on Radiation Sensitivity in IDH-Mutant Astrocytomas

Introduction: IDH-mutant astrocytomas represent the most prevalent primary tumors in young adults. A substantial minority of these tumors exhibit the deletion of CDKN2A (Cyclin-Dependent Kinase Inhibitor Gene 2A). Homozygous deletion of this gene– which encodes the tumor suppressor protein p16 – is associated with a malignant phenotype and poorer prognosis in IDH-mutant astrocytoma.

CDKN2A deletions are primarily observed in tumors that have received radiation therapy (RT), suggesting a mechanistic relationship between RT and subsequent deletion. Here, we sought to determine whether this relationship could be due the emergence of radioresistance in p16 deleted tumors cells.

This study investigates the influence of CDKN2A deletion on IDH-mutant astrocytoma response to RT.

Methods: The antitumor effect of RT was evaluated in vitro using patient-derived IDH-mutant astrocytoma cells MGG152. A homozygous CDKN2A deletion was engineered in this parental line, creating a paired line to permit an isogenic comparison between CDKN2A intact versus CDKN2A deleted tumor cells. Differences in cell viability after a predetermined incubation period were examined and relevant statistical comparisons performed.

Results: Dose-response curves in response to radiation therapy, comparing CDKN2A intact and deleted cell lines, were generated. Both CDKN2A intact and deleted cell lines exhibited significant reductions in viability following radiation exposure (p < 0.001), with CDKN2A-deleted cells displaying a slightly greater sensitivity (p = 0.022).

Conclusion : Our findings provide evidence that p16 does not confer radioresistance in IDH-mutant astrocytomas.