The contribution of methylation profiling in neuropathological diagnosis of central nervous system tumors in children, adolescent and young adults

Methylation of CpG islands plays a crucial role in the regulation of gene expression. The study of DNA methylation profiles offers deep insights into key oncogenic processes and facilitates the differentiation of tumor entities at the epigenetic level. Methylation profiling was performed on 8 CNS tumors (6 children, 1 adolescent, 1 young adult) with inconclusive diagnoses, available frozen tissue, and surgeries dating back over 5 years. Our goal was to correlate the resulting methylation classes with the clinical-radiological data and to evaluate the diagnostic and prognostic power of this analysis. The resulting molecularly defined diagnoses were: pilocytic astrocytoma (3 cases), pilocytic astrocytoma subclass <i>FGFR1</i> altered (1 case), ganglioglioma (2 cases), diffuse leptomeningeal glioneuronal tumor subtype 1 (1 case), and diffuse midline glioma <i>H3.3K27</i>-altered, subtype <i>H3K27</i> mutant or <i>EZHIP</i>-expressing (1 case). Clinico-pathological features of each tumor in our series are discussed. The clinical behavior was consistent with the molecular diagnosis in all cases but one that was lost to follow-up. In our series, the initial diagnostic failure in 3 of the 8 cases was due to the fact that the pathological entities-diffuse midline glioma, H3 K27-altered, pilocytic astrocytoma with FGFR1 alteration and diffuse leptomeningeal glioneuronal tumor -had not yet been fully characterized or widely recognized in the literature at the time of diagnosis. In the remaining cases, the lack of distinctive histopathological features hindered a definitive diagnosis. In conclusion, according to our experience, DNA methylation profile analysis represents a very attractive diagnostic tool and provides important support for the diagnosis and classification of CNS tumors.