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. 2024 Jun 3;26(6):1042-1051.
doi: 10.1093/neuonc/noae009.

Prognostic value of DNA methylation subclassification, aneuploidy, and CDKN2A/B homozygous deletion in predicting clinical outcome of IDH mutant astrocytomas

Kristyn Galbraith  1 , Mekka Garcia  2 , Siyu Wei  3 , Anna Chen  4 , Chanel Schroff  1 , Jonathan Serrano  1 , Donato Pacione  5 , Dimitris G Placantonakis  5 , Christopher M William  1 , Arline Faustin  1 , David Zagzag  1 , Marissa Barbaro  6 , Maria Del Pilar Guillermo Prieto Eibl  6 , Mitsuaki Shirahata  1 , David Reuss  7   8 , Quynh T Tran  9 , Zahangir Alom  9 , Andreas von Deimling  7   8 , Brent A Orr  9 , Erik P Sulman  10   11 , John G Golfinos  5 , Daniel A Orringer  5 , Rajan Jain  5 , Evan Lieberman  4 , Yang Feng  3 , Matija Snuderl  1   11
Affiliations

Prognostic value of DNA methylation subclassification, aneuploidy, and CDKN2A/B homozygous deletion in predicting clinical outcome of IDH mutant astrocytomas

Kristyn Galbraith et al. Neuro Oncol. .

Abstract

Background: Isocitrate dehydrogenase (IDH) mutant astrocytoma grading, until recently, has been entirely based on morphology. The 5th edition of the Central Nervous System World Health Organization (WHO) introduces CDKN2A/B homozygous deletion as a biomarker of grade 4. We sought to investigate the prognostic impact of DNA methylation-derived molecular biomarkers for IDH mutant astrocytoma.

Methods: We analyzed 98 IDH mutant astrocytomas diagnosed at NYU Langone Health between 2014 and 2022. We reviewed DNA methylation subclass, CDKN2A/B homozygous deletion, and ploidy and correlated molecular biomarkers with histological grade, progression free (PFS), and overall (OS) survival. Findings were confirmed using 2 independent validation cohorts.

Results: There was no significant difference in OS or PFS when stratified by histologic WHO grade alone, copy number complexity, or extent of resection. OS was significantly different when patients were stratified either by CDKN2A/B homozygous deletion or by DNA methylation subclass (P value = .0286 and .0016, respectively). None of the molecular biomarkers were associated with significantly better PFS, although DNA methylation classification showed a trend (P value = .0534).

Conclusions: The current WHO recognized grading criteria for IDH mutant astrocytomas show limited prognostic value. Stratification based on DNA methylation shows superior prognostic value for OS.

Keywords: DNA methylation; IDH mutant astrocytoma; grading; molecular; prognosis.

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Conflict of interest statement

D.G.P. and NYU Grossman School of Medicine own an EU and Hong Kong patent titled “Method for treating high-grade gliomas,” which is unrelated to the context of this manuscript. D.G.P. has received consultant fees from Tocagen, Synaptive Medical, Monteris, Robeaute, and Advantis. M.S. is a scientific advisor and shareholder of C2i Genomics, Heidelberg Epignostix and Halo Dx, and a scientific advisor of Arima Genomics, and InnoSIGN, and received research funding from Lilly USA. A.v.D. is a scientific advisor and shareholder of Heidelberg Epignostix. Other authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.
Copy number plots. We analyzed ploidy using the copy number plots from the DNA methylation analysis using previously published methods.,, Cases were stratified into complex copy number plot, notably without CDKN2A/B homozygous deletion (A) and simple copy number plot (B). CDKN2A/B homozygous deletion (arrow) status on chromosome 9p was also analyzed via the copy number plot (C).
Figure 2.
Figure 2.
Cohort stratified by biomarkers. (A) Histology and (B) DNA methylation classification into clinically validated low- (A_IDH_LG) and high-grade (A_IDH_HG) subgroups. (C) Association of WHO grade and DNA methylation class. (D) WHO grade 2 tumors and the A_IDH_LG methylation class were more likely to have simple copy number plots (85% and 74%, respectively). The WHO grade 4 tumors and the A_IDH_HG methylation class were more likely to have complex copy number structure (86% and 85%, respectively). The WHO grade 3 tumors were evenly split between simple (45%) and complex copy number plots (55%). (E) The majority of WHO grade 2 tumors and the A_IDH_LG methylation class showed maintenance of CDKN2A/B (85% and 79%, respectively). Similar to the DNA methylation classification, WHO grade 3 tumors were almost evenly separated into a CDKN2A/B retained subgroup (42%) and a CDKN2A/B homozygous deletion subgroup (58%). WHO grade 4 tumors did not show enrichment for the CDKN2A/B retained (46%) or deleted categories (54%). The majority of the A_IDH_HG methylation class had CDKN2A/B homozygous deletion (68%), while 32% maintained CDKN2A/B. (F) In our cohort, only 16% of cases with simple copy number plots had isolated homozygous deletion of CDKN2A/B, while 63% of cases with complex copy number had CDKN2A/B deletion (63%).
Figure 3.
Figure 3.
Survival data. Survival analysis showed that there was no significant difference in overall survival (OS) in IDH1/2 mutant astrocytoma when stratified by WHO grade alone (P value = .0699) (A) or by copy number complexity (P value = .0588) (D). OS was significantly different when patients were stratified either by CDKN2A/B homozygous deletion or by DNA methylation subclass (P value = .0286 and .0016, respectively) (B and C). None of the molecular biomarkers were associated with significantly better progression free survival (PFS), although DNA methylation classification showed a trend to significance (P value = .0534).
Figure 4.
Figure 4.
IDH mutant WHO grade 3 astrocytoma overall and progression free survival (PFS) stratified by methylation subclass (A), CDKN2A homozygous deletion (B), and copy number (C). Overall survival (OS) was significantly different only using DNA methylation as a marker (P value = .0204), while PFS was not. There was no statistically significant difference between OS and PFS in WHO grade 3 tumors that were stratified by CDKN2A/B homozygous deletion (P value = .3515 and .0954, respectively) or copy number complexity alone (P value = .2039 and .2465, respectively).
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