SWI/SNF chromatin remodeling complex alterations in meningioma

Abstract

Purpose: While SWI/SNF chromatin remodeling complex alterations occur in approximately 20% of cancer, the frequency and potential impact on clinical outcomes in meningiomas remains to be comprehensively elucidated.

Methods: A large series of 255 meningiomas from a single institution that was enriched for high grade and recurrent lesions was identified. We performed next-generation targeted sequencing of known meningioma driver genes, including NF2, AKT1, PIK3CA, PIK3R1, and SMO and SWI/SNF chromatin remodeling complex genes, including ARID1A, SMARCA4, and SMARCB1 in all samples. Clinical correlates focused on clinical presentation and patient outcomes are presented.

Results: The series included 63 grade I meningiomas and 192 high-grade meningiomas, including 173 WHO grade II and 19 WHO grade III. Samples from recurrent surgeries comprised 37.3% of the series. A total of 41.6% meningiomas were from the skull base. NF2, AKT1, PIK3CA, PIK3R1, and SMO were mutated in 40.8, 7.1, 3.5, 3.9, and 2.4% of samples, respectively. ARID1A, SMARCA4, and SMARCB1 mutations were observed in 17.3, 3.5, and 5.1% of samples, respectively. A total of 68.2% of ARID1A-mutant meningiomas harbored a p.Gln1327del in-frame deletion. ARID1A mutations were seen in 19.1% of Grade I, 16.8% of Grade II, and 15.8% of Grade III meningiomas (P = 0.9, Fisher's exact). Median overall survival was 16.3 years (95% CI 10.9, 16.8). With multivariable analysis, the presence of an ARID1A mutation was significantly associated with a 7.421-fold increased hazard of death (P = 0.04).

Conclusion: ARID1A mutations occur with similar frequency between low and high-grade meningiomas, but ARID1A mutations are independently prognostic of worse prognosis beyond clinical and histopathologic features.

Keywords: ARID1A; Chromatin remodeling; Epigenetic; Genomic; Meningioma; SWI/SNF.

Fig. 1

Clinical characteristics and mutation status by sample

Fig. 2

Kaplan–Meier curves for a overall survival and b progression-free survival reported in years. Median overall survival: 16.3 years (95% CI 10.9, 16.8). Median progression-free survival: 4.4 years (95% CI 2.6, 5.0)

Fig. 3

Lollipop plots visualizing protein alterations in NF2, AKT1, PIK3CA, PIK3R1, and SMO. Y-axis lists the number of protein alterations

Fig. 4

Lollipop plots visualizing protein alterations in ARID1A, SMARCA4, and SMARCB1. Y-axis lists the number of protein alterations