DNA methylation profiling of CNS tumors; implications for clinical diagnostics

Abstract

Diffuse gliomas and meningiomas are the most common primary tumors of the central nervous system (CNS) in adults and these tumors cause significant morbidity and mortality worldwide. Deregulation of the epigenetic mechanisms, e.g. in the form of aberrant changes of DNA methylation patterns, are important for the formation and development of many diseases including cancer. Genome-wide DNA methylation profiling is an emerging molecular technique that offers a new way for characterization of CNS tumors with potential use in routine clinical diagnostics. In this thesis, we used DNA methylation profiling for evaluation of patient diagnosis and prognosis and further provide new insights into intratumor heterogeneity, highlighting the potential implications that this could bring into the clinical setting. In Paper I, we assessed the value of using DNA methylation profiling as a diagnostic tool for molecular classification of diffuse lower-grade gliomas. We demonstrated that methylation profiling provided accurate diagnostic and prognostic information and enabled a reliable molecular classification of the tumors according to the World Health Organization classification criteria. In Paper II, we studied DNA methylation profiles across distinct regions of glioblastomas and found methylation subclass differences within the tumors as well as variable methylation status of the clinical prognostic and predictive biomarker MGMT. In Paper III, we further explored DNA methylation and chromosomal copy number variability within adult-type diffuse gliomas and meningiomas and shed light on the effect of varying tumor cell content on methylation analyses. Diffuse gliomas and high-grade meningiomas were characterized by spatial methylation and chromosomal heterogeneity after accounting for tumor purity. In addition, we found heterogeneity of the clinical biomarker CDKN2A/B homozygous deletion in IDH-mutant gliomas. In Paper IV, we investigated DNA methylation changes during progression of IDH-mutant gliomas. The tumors accumulated methylation alterations over time, but methylation patterns were mostly maintained upon recurrence. In conclusion, we demonstrated the potential of using DNA methylation profiling for improved CNS tumor diagnostics and prognostics. We further provided a better understanding of the methylation and chromosomal heterogeneity in diffuse gliomas and meningiomas, which could affect the clinical diagnosis and treatment management of these patients.