DNA methylation profiling to predict recurrence risk in meningioma: development and validation of a nomogram to optimize clinical management

Abstract

Background: Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma.

Methods: DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts.

Results: The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03-0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8-7.2, P < 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22-0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3-11.1, P < 0.001) with clinical implications.

Conclusions: The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone.

Keywords: meningioma; methylation; nomogram; predictor; recurrence.

Fig. 1

Comparison of grade-based and methylome-based RFS predictor performance. Data presented are time-dependent ROC curves and average AUC as well as ΔAUC (DAUC) with 95% CI using 10 000 bootstrap resampling validation approach for methylome-based and grade-based predictors in the (A) first validation cohort, (B) second validation cohort, (C) third validation cohort, and (D) combined validation cohorts.

Fig. 2

RFS analysis of the first validation cohort (A), second validation cohort (B), and (C) third validation cohort using the 5-year methylome-based RFS predictor, based on separation into distinct risk groups by median.

Fig. 3

Frequency of copy number alterations across the genome stratified in risk groups according to the methylome-based predictor. Groups correspond to same groups seen in Fig. 2.

Fig. 4

Survival analysis of all WHO grade I (A), WHO grade II (B) and WHO grade III (C) tumors in all 3 validation cohorts stratified by methylation-based predictor risk groups.

Fig. 5

Nomogram to predict 5-year recurrence risk in meningiomas. (A) Total points generated from scoring of methylome-based RFS predictor, WHO grade, and Simpson grade are tallied in the calculator and correlated to 5-year RFS in the nomogram in the risk nomogram. (B) Time-dependent average AUC with 95% CI as well as ΔAUC (dAUC) with 95% CI using 10 000 bootstrap resampling validation approach generated for the meningioma recurrence score and a nomogram using clinical factors alone in the first and third validation cohorts as well as both combined validation cohorts. (C) Calibration curve of the nomogram to predict RFS at 5 years in the combined validation cohort. The observed RFS is plotted on the y-axis and nomogram predicted probability is plotted on the x-axis.

Fig. 6

The meningioma recurrence score identifies 2 risk groups (high risk vs low risk) that may help individualize adjuvant management decisions such as the need for radiation therapy in patients with meningiomas. Patient tumor samples can be interrogated for DNA methylation profile of selected 9529 probes, and a 5-year methylome-based RFS predictor score is generated. This score is combined with tumor WHO grade and Simpson grade in the meningioma recurrence score to develop an individualized probability of 5-year RFS.