Chromosome 1p loss and 1q gain are highly prognostic and can inform WHO grading of meningioma

Introduction: The CNS WHO grade of meningioma was updated in 2021 to include rare molecular features, namely homozygous deletions of CDKN2A/CDKN2B and TERT promotor mutations. Previous work including the recent cIMPACT-NOW statement have discussed the potential value of including chromosomal copy number alterations (CNAs) to help refine current grading. The objective of this work was to identify chromosomal CNAs which could be used to improve the current CNS WHO grading of meningioma.

Methods: Using a multi-center cohort of 1964 meningiomas, DNA methylation was used to infer chromosomal arm-level copy number profile, with a subset (n=211) validated using whole exome sequencing. Regularized Cox regression was used to identify chromosomal CNAs independently associated with both post-surgical and post-RT PFS after adjusting for CNS WHO grade and extent of resection. Progression-free survival was compared between CNS WHO grades stratified by relevant CNAs to assess their potential supplemental role within modern WHO criteria.

Results: We demonstrate that loss of chromosome 1p in CNS WHO grade 1 meningiomas was associated with significantly worse outcomes compared to cases without loss of 1p (median PFS 5.83 [95% CI 4.36-Inf] vs 34.54 [16.01-Inf] years, log-rank p < 0.001). Outcome of patients with CNS WHO grade 1 tumours with loss of chromosome 1p was comparable to CNS WHO grade 2 tumours (median PFS 4.48 [4.09-5.18] years). Combined loss of chromosome 1p and gain of chromosome 1q portended outcomes which were highly concordant with CNS WHO grade 3 cases regardless of initial grade (median PFS 2.23 [1.28-Inf] years for WHO grade 1 and 1.90 [1.23-2.25] years for WHO grade 2, compared to 2.27 [1.68-3.05] years in all WHO grade 3 cases).

Conclusion : Our findings highlight a role for cytogenetic profiling in the next iteration of CNS WHO grading, with a specific focus on chromosome 1p loss and 1q gain. We advocate for chromosome 1p loss as a criterion for a CNS WHO grade of 2 and the addition of 1q gain as a criterion for a CNS WHO grade of 3.