Combined NF2/PTEN mutations as predictors of meningioma aggressiveness.
Authors: Om H. Gandhi, Sonia Ajmera, Antonio Corral Tarbay, Saawan Patel, Sneha Sai Mannam, Ritesh Karsalia, Christina Jackson
Journal: Journal of Clinical Oncology (2024)

e14044 Background: In meningiomas, loss of the NF2 tumor suppressor gene function leads to dysregulation of cell proliferation and tumor formation. PTEN, another tumor suppressor gene correlated with worse prognosis in tumors like gliomas, has also been reported in meningiomas, but the impact of its mutation alone or in conjunction with NF2 loss on outcomes in these tumors is unexplored. We aimed to evaluate whether dual NF2/PTEN mutations comprise a more aggressive meningioma phenotype compared to tumors with only NF2 mutations. Identifying this high-risk genetic profile could allow for preventative and individualized treatment of these aggressive meningiomas. Methods: We reviewed patients who underwent meningioma resection at our institution from January 2018 through October 2022. Demographic information, tumor characteristics, pre- and post-operative clinical characteristics, and outcomes were collected. Meningioma specimens were analyzed by immunohistochemistry for WHO grading and Ki67 proliferation index and by sequencing for genomic alterations. We performed multivariable logistic regression analyses to identify clinical outcomes associated with proliferation index and genetic mutations. Results: We identified NF2 mutations in 24 meningiomas and dual NF2/PTEN mutations in 7 meningiomas. Mutation rates did not significantly differ based on demographic factors including sex, age, race, socioeconomic status, or prior cranial radiation status (p&gt;0.05). The majority of tumors with these mutations (93%) were in non-skull base regions (i.e. convexity, parafalcine). Tumors with both NF2 and PTEN mutations were more likely to be WHO grade III tumors than those with the NF2 mutation alone (29% versus 9%). Tumors with dual mutations had higher likelihood of having Ki67 proliferation indices ≥ 10% (OR 5.98, p&lt;0.01). While higher Ki67 index was significantly associated with features of more aggressive tumors including higher WHO grade and recurrence rates, dual mutation in NF2 and PTEN is associated with higher rate of recurrence (OR 13.13, p&lt;0.001) and mortality (OR 5.14, p&lt;0.05) compared to NF2 irrespective of Ki67 index. Notably, patients with mutations in NF2 alone or both NF2/PTEN did not differ in preoperative Karnofsky performance score, Simpson resection grade, or presence of post operative residual tumor. Conclusions: Our results demonstrated that concomitant NF2 and PTEN mutations in meningiomas were associated with higher WHO grades, tumor proliferation indices, recurrence rates, and mortality rates. This finding suggests that NF2/PTEN mutated meningiomas represent a distinct subset of tumors that demonstrate a more aggressive clinical and histopathological phenotype that may require more aggressive treatment and closer surveillance. Further investigation is warranted to confirm the prognostic relevance of NF2/PTEN mutations in meningioma and elucidate their underlying molecular mechanisms.