JS04.5.A HEMIZYGOUSCDKN2A DELETION CONFERS WORSE SURVIVAL OUTCOMES IN IDH-MUTANT GLIOMAS

Abstract

Abstract BACKGROUND The tumor suppressor gene CDKN2A is frequently deactivated in cancer. Homozygous CDKN2A deletion is a Grade 4 defining criterion for IDH-mutant gliomas. However, the prognostic value of hemizygous CDKN2A deletions is unclear. We assessed CNV profiles of 1238 initial and 479 recurrent IDHmut gliomas to evaluate the association of CDKN2A hemizygous deletions with overall survival (OS) outcomes. MATERIAL AND METHODS The GLASS primary/recurrent glioma dataset was used to infer CDKN2A status with DNAseq (n=210) and DNA methylation array (n=100) data. Validation was conducted using DFCI, MSKCC, TCGA and DKFZ cohorts. RESULTS Longitudinal analyses of IDH-mutant gliomas without 1p-/19q-codeletion showed significant increases in CDKN2A homozygous deletion from n=6 to n=23 (5% to 20%, P=0.0001, Fisher’s-exact test) and hemizygous deletion from n=19 to n=34 (17% to 30%, P=0.002) at recurrence. CDKN2A hemizygous deletions were significantly associated with poor OS at initial diagnosis (P<0.0001, log-rank test) and recurrence (P<0.0001), remaining significant in multivariable cox regression model that accounted for age, treatment with radiotherapy and/or alkylating agents, and 1p/19q-codeletion status: HR 2.40 (95%-CI: 1.31-4.37, P=0.004). Validation in independent datasets confirmed increased frequencies of CDKN2A hemizygous deletions in recurrent cases as well as the association between CDKN2A hemizygous deletion and worse OS in IDHmut gliomas. Using the DKFZ DNA methylation profiling dataset we further confirmed that CDKN2A status can be accurately assessed through DNAseq and DNA methylation array profiling. CONCLUSION CDKN2A hemizygous deletion is associated with significantly worse OS in initial and recurrent IDHmut gliomas. Similar to CDKN2A homozygous deletion, CDKN2A hemizygous deletion is enriched in post-treatment, recurrent IDHmut gliomas, confirming the value of CDKN2A status (re-)assessment in recurrences. Our results highlight the importance of incorporating CDKN2A status in diagnostic workup to inform prognosis and treatment strategies, revealing the previously unrecognized prognostic value of hemizygous CDKN2A deletions.