Faculty Collaboration Database

Modern molecular profiling recontextualizes the NRG/RTOG 0539 trial and reveals hidden high-risk and radiotherapy-resistant meningiomas. Neuro Oncol 2026 Jul 01;28(7):1727-1740

Date

05/17/2026

Pubmed ID

42143623

Pubmed Central ID

PMC13338323

DOI

10.1093/neuonc/noag081

Scopus ID

2-s2.0-105043866456 (requires institutional sign-in at Scopus site)

Abstract

BACKGROUND: Meningiomas exhibit clinical heterogeneity. Radiotherapy (RT) remains the only adjuvant therapy, but tumor-control is variable, and biomarkers are limited. NRG/RTOG-0539 is the first prospective phase 2 trial to stratify meningioma patients for adjuvant RT based on clinical risk. Here, we apply modern molecular tools to this cohort and identify correlates of RT response.

METHODS: Tumor tissue from 100 RTOG-0539 patients was profiled using DNA methylation arrays, RNA sequencing, and whole-exome sequencing. Recurrence scores, Molecular Groups, gene expression, and copy number alterations were compared across clinical groups and between RT responders and non-responders; non-response was defined as progression or death within 3 years.

RESULTS: Modern grading criteria, including brain invasion, TERT mutation, CDKN2A/B deletion, and 1p/1q status, would reclassify 10% of tumors and alter treatment group assignment in 7%. Non-responders to RT exhibited more frequent 1p and 14q loss, and more copy number alterations. Transcriptomic and epigenetic profiling revealed immune-related signatures in responders and cell cycle-related pathways in non-responders, several of which overlapped with targets of vorinostat, a histone deacetylase inhibitor previously validated in aggressive meningioma models. The Proliferative Molecular Group was an independent predictor of post-RT recurrence in multivariable analysis, outperforming WHO grade.

CONCLUSION: Multi-omic analysis of the NRG/RTOG-0539 cohort shows that updated WHO grading criteria, incorporating molecular and cytogenetic features, improve risk stratification. However, molecular classification, particularly the Proliferative group, remains an independent and stronger predictor of RT response. These findings support integrating molecular biomarkers alongside modern grading frameworks to guide treatment and trial design in meningioma.

CLINICAL TRIAL INFORMATION: NCT00895622.

Author List

Yefet LS, Landry AP, Rogers CL, Wang JZ, Liu J, Patil V, Gui C, Ajisebutu A, Ellenbogen Y, Wei Q, Singh O, Mansouri S, Szot C, Jordan RC, Barani IJ, Straza MW, Shu HG, Pointer KB, Hunter G, Panet-Raymond V, Shi W, Perlow HK, Kavanagh BD, Gunter T, Robinson C, Pugh SL, Dicker AP, Mehta MP, Chakravarti A, Nassiri F, Aldape K, Zadeh G

Author

Michael W. Straza MD, PhD Associate Professor in the Radiation Oncology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Biomarkers, Tumor
DNA Copy Number Variations
DNA Methylation
Female
Follow-Up Studies
Gene Expression Profiling
Humans
Male
Meningeal Neoplasms
Meningioma
Middle Aged
Neoplasm Recurrence, Local
Prognosis
Prospective Studies
Radiotherapy, Adjuvant