Hemizygous deletion of cyclin-dependent kinase inhibitor 2A/B with p16 immuno-negative and methylthioadenosine phosphorylase retention predicts poor prognosis in IDH-mutant adult glioma

Background. Homozygous deletion of the tumor suppression genes cyclin‑dependent kinase inhibitor 2A/B (CDKN2A/B) is a strong adverse prognostic factor in IDH‑mutant gliomas, particularly astrocytoma. However, the impact of hemizygous deletion of CDKN2A/B is unknown. Furthermore, the influence of CDKN2A/B status in IDH‑ mutant and 1p/19q‑codeleted oligodendroglioma remains controversial. We examined the impact of CDKN2A/B status classification, including hemizygous deletions, on the prognosis of IDH‑mutant gliomas. Methods. We enrolled 101 adults with IDH‑mutant glioma between December 2002 and November 2021. CDKN2A/B deletion was evaluated with multiplex ligation‑dependent probe amplification (MLPA). Immunohistochemical anal‑ ysis of p16/MTAP and promoter methylation analysis with methylation‑specific MLPA was performed for cases with CDKN2A/B deletion. Kaplan − Meier plots and Cox proportion hazards model analyses were performed to evaluate the impact on overall (OS) and progression‑free survival. Results. Of 101 cases, 12 and 4 were classified as hemizygous and homozygous deletion, respectively. Immunohistochemistry revealed p16‑negative and MTAP retention in cases with hemizygous deletion, whereas homozygous deletions had p16‑negative and MTAP loss. In astrocytoma, OS was shorter in the order of homozy‑ gous deletion, hemizygous deletion, and copy‑neutral groups (median OS: 38.5, 59.5, and 93.1 months, respec‑ tively). Multivariate analysis revealed hazard ratios of 9.30 (P = .0191) and 2.44 (P = .0943) for homozygous and hemizygous deletions, respectively. Conclusions. CDKN2A/B hemizygous deletions exerted a negative impact on OS in astrocytoma. Immunohistochemistry of p16/MTAP can be utilized to validate hemizygous or homozygous deletions in combina‑ tion with conventional molecular diagnosis.