Molecular characteristics and prognostic biomarkers of central neurocytoma

Abstract BACKGROUND Central neurocytomas (CN) are intraventricular brain tumors predominantly arising in young adults. Long-term prognosis is favorable in the majority of cases, whereas a considerable proportion of patients experience disease progression. Progression risk is currently assessed morphologically based on the presence of histological signs of atypia and/or an elevated ki67 proliferation index (>3%). The molecular profile and etiology of CN remains elusive and molecular biomarkers for risk stratification have not been identified yet. MATERIAL AND METHODS We analyzed a retrospective multi-institutional cohort of 108 CNs by genome-wide DNA methylation profiling. DNA whole exome sequencing was performed in 12 cases. Follow-up information was available for 45 patients. RESULTS The histological diagnosis of neurocytoma was epigenetically confirmed in 96 cases. 12/108 cases (11%) were assigned to another methylation class based on the v12.5 Heidelberg Brain Tumor Classifier. Median age at diagnosis was 29 years, distribution among sexes was equal. Based on morphology and immunohistochemistry, tumors were diagnosed as classical CN (n = 71), CN with increased proliferation (n = 10) and atypical CN (n = 15). In 49/72 cases (68%, NA=24), an elevated Ki67 above 3% was reported. DNA whole exome sequencing revealed no recurrent genetic alterations. Most copy number profiles were balanced (n = 87), while some cases (n = 9) showed individual chromosomal alterations (e.g. chr. +5, n = 3). Tumor recurrence was observed in 16/45 (36%, NA = 51) of cases. Median progression-free survival (PFS) after the initial diagnosis was 72 months, none of the patients died (observation time: range 3 - 141 months). In 16 cases, surgery was followed by adjuvant radiotherapy, predominantly in patients with subtotal resection (STR: n = 11, 69%; GTR: n = 5). There was no significantly different outcome between classical and atypical CNs (n = 45; median PFS 73 months vs. 26 months, p-value = 0.067) and cases with low vs. elevated Ki67 (n = 45; median PFS NA vs. 72 months, p-value = 0.44). CONCLUSION Preliminary data of our study indicate that histological diagnosis and Ki67 proliferation rate were not associated with PFS in epigenetically defined neurocytomas. Further research using clinical and molecular covariates is necessary to identify novel biomarkers to predict recurrence risk and benefit from adjuvant radiotherapy.