DNA methylation profiling of meningiomas highlights clinically distinct molecular subgroups

• Published in: Journal of neuro-oncology Vol. 161; no. 2; pp. 339 - 356
• Main Authors: Singh, Jyotsna, Sharma, Ravi, Shukla, Nidhi, Narwal, Priya, Katiyar, Amit, Mahajan, Swati, Sahu, Saumya, Garg, Ajay, Sharma, Mehar C., Suri, Ashish, sarkar, Chitra, Suri, Vaishali
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.01.2023; Springer Nature B.V
• Subjects: AKT1 protein; Benign; Brain cancer; Brain tumors; Chromosome 22; Chromosome Aberrations; Chromosome deletion; Classification; Copy number; DNA fingerprinting; DNA Methylation; Genomes; Histones - genetics; Humans; Medicine; Medicine & Public Health; Meningeal Neoplasms - genetics; Meningeal Neoplasms - pathology; Meningioma; Meningioma - genetics; Meningioma - pathology; Mutation; Neurology; Oncology; Survival; Survival analysis; Methylation subgroups; Targeted sequencing; H3K27me3 expression; Methylation profiling; Unsupervised hierarchical clustering; DKFZ classifier
• ISSN: 0167-594X; 1573-7373; 1573-7373
• DOI: 10.1007/s11060-022-04220-3

Background Introduction of the classification of brain tumours based on DNA methylation profile has significantly changed the diagnostic approach. Due to the paucity of data on the molecular profiling of meningiomas and their clinical implications, no effective therapies and new treatments have been implemented. Methods DNA methylation profiling, copy number analysis, targeted sequencing and H3K27me3 expression was performed on 35 meningiomas and 5 controls. Results Unsupervised hierarchical clustering ( UHC) analysis revealed four distinct molecular subgroups: Malignant; Intermediate; Benign A, and Benign B. Molecular heterogeneity was observed within the same grade as the Intermediate, Benign A, and Benign B subgroups were composed of WHO grade 1 as well as grade 2 cases. There was association of mutations with distinct methylation subgroups (NF2, AKT1, SMO, TRAF7 and pTERT). Loss of chromosome 22q was observed across all subgroups. 1p/14q co-deletion was seen in 50% of malignant and intermediate while CDKN2A loss was predominantly observed in malignant subgroup (50%). Majority of malignant (75%) and a small proportion of other subgroups (Intermediate: 25%, Benign A: 38.5%, and Benign B: 20%) harboured H3K27me3 loss. 38,734 genes were dysregulated amongst the four subgroups. DKFZ classified 71% cases with acceptable score. On survival analysis, methylation profiling had significant impact on progression-free-survival in WHO grade1 and 2 meningiomas (p = 0.0051). Conclusion Genome-wide DNA methylation profiling highlights clinically distinct molecular subgroups and heterogeneity within the same grade of meningiomas. Molecular profiling can usher in a paradigm shift in meningioma classification, prognostic prediction, and treatment strategy.