Association between tumor mutations and meningioma recurrence in Grade I/II disease

Jonathan T. Dullea1, Vikram Vasan1, John W. Rutland1, Corey M. Gill1, Danielle Chaluts1, Daniel Ranti1, Ethan Ellis4, Varun Subramanium1, Annie Arrighi-Allisan1, Yayoi Kinoshita2, Russell B. McBride2,3, Joshua Bederson1, Michael Donovan2, Robert Sebra4,5, Melissa Umphlett2 and Raj K. Shrivastava1

1 Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA

2 Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA

3 The Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA

4 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA

5 Sema4, A Mount Sinai Venture, Stamford, CT 06902, USA

Correspondence to:

Jonathan T. Dullea, email: [email protected]

Keywords: meningioma; molecular genomics; POLE; ATM; CREBBP

Received: June 14, 2022 Accepted: November 29, 2022 Published: December 09, 2022

ABSTRACT

Background: Meningiomas are common intracranial tumors with variable prognoses not entirely captured by commonly used classification schemes. We sought to determine the relationship between meningioma mutations and oncologic outcomes using a targeted next-generation sequencing panel.

Materials and Methods: We identified 184 grade I and II meningiomas with both >90 days of post-surgical follow-up and linked targeted next-generation sequencing. For mutated genes in greater than 5% of the sample, we computed progression-free survival Cox-regression models stratified by gene. We then built a multi-gene model by including all gene predictors with a p-value of less than 0.20. Starting with that model, we performed backward selection to identify the most predictive factors.

Results: ATM (HR = 4.448; 95% CI: 1.517–13.046), CREBBP (HR = 2.727; 95% CI = 1.163–6.396), and POLE (HR = 0.544; HR = 0.311–0.952) were significantly associated with alterations in disease progression after adjusting for clinical and pathologic factors. In the multi-gene model, only POLE remained a significant predictor of recurrence after adjusting for the same clinical covariates. Backwards selection identified recurrence status, resection extent, and mutations in ATM (HR = 7.333; 95% CI = 2.318–23.195) and POLE (HR = 0.413; 95% CI = 0.229–0.743) as predictive of recurrence.

Conclusions: Mutations in ATM and CREBBP were associated with accelerated meningioma recurrence, and mutations in POLE were protective of recurrence. Each mutation has potential implications for treatment. The effect of these mutations on oncologic outcomes and as potential targets for intervention warrants future study.

PII: 570