Respective roles of Pik3ca mutations and cyproterone acetate impregnation in mouse meningioma tumorigenesis.

Despite their rarity, PIK3CA mutations in meningiomas have raised interest as potentially targetable, ubiquitous mutations owing to their presence in sporadic benign and malignant tumors but also in hormone-related cases. Using new genetically engineered mouse models, we here demonstrate that Pik3ca mutations in postnatal meningeal cells are sufficient to promote meningioma formation but also tumor progression in mice. Conversely, hormone impregnation, whether alone or in association with Pik3ca and Nf2 mutations, fails to induce meningioma tumorigenesis while promoting breast tumor formation. We then confirm in vitro the effect of Pik3ca mutations but not hormone impregnation on the proliferation of primary cultures of mouse meningeal cells. Finally, we show by exome analysis of breast tumors and meninges that hormone impregnation promotes breast tumor formation without additional somatic oncogenic mutation but is associated with an increased mutational burden on Pik3ca-mutant background. Taken together, these results tend to suggest a prominent role of Pik3ca mutations over hormone impregnation in meningioma tumorigenesis, the exact effect of the latter is still to be discovered.

Somatic PIK3CA Mutations in Sporadic Cerebral Cavernous Malformations.

BACKGROUND: Cerebral cavernous malformations (CCMs) are common sporadic and inherited vascular malformations of the central nervous system. Although familial CCMs are linked to loss-of-function mutations in KRIT1 (CCM1), CCM2, or PDCD10 (CCM3), the genetic cause of sporadic CCMs, representing 80% of cases, remains incompletely understood. METHODS: We developed two mouse models harboring mutations identified in human meningiomas with the use of the prostaglandin D2 synthase (PGDS) promoter. We performed targeted DNA sequencing of surgically resected CCMs from patients and confirmed our findings by droplet digital polymerase-chain-reaction analysis. RESULTS: We found that in mice expressing one of two common genetic drivers of meningioma - Pik3ca H1047R or AKT1 E17K - in PGDS-positive cells, a spectrum of typical CCMs develops (in 22% and 11% of the mice, respectively) instead of meningiomas, which prompted us to analyze tissue samples from sporadic CCMs from 88 patients. We detected somatic activating PIK3CA and AKT1 mutations in 39% and 1%, respectively, of lesion tissue from the patients. Only 10% of lesions harbored mutations in the CCM genes. We analyzed lesions induced by the activating mutations Pik3ca H1074R and AKT1 E17K in mice and identified the PGDS-expressing pericyte as the probable cell of origin. CONCLUSIONS: In tissue samples from sporadic CCMs, mutations in PIK3CA were represented to a greater extent than mutations in any other gene. The contribution of somatic mutations in the genes that cause familial CCMs was comparatively small. (Funded by the Fondation ARC pour la Recherche contre le Cancer and others.).

Validation of a scoring system to evaluate the risk of rapid growth of intracranial meningiomas in neurofibromatosis type 2 patients.

OBJECTIVE: Intracranial meningiomas occur in about half of neurofibromatosis type 2 (NF2) patients and are very frequently multiple. Thus, estimating individual meningiomas' growth rates is of great interest to tailor therapeutic interventions. The Asan Intracranial Meningioma Scoring System (AIMSS) has recently been published to estimate the risk of tumor growth in sporadic meningiomas. The current study aimed to determine predictors of rapid meningioma growth in NF2 patients and to evaluate the AIMSS score in a specific NF2 cohort. METHODS: The authors performed a retrospective analysis of 92 NF2 patients with 358 measured intracranial meningiomas that had been observed prospectively between 2012 and 2018. Tumor volumes were measured at diagnosis and at each follow-up visit. The growth rates were determined and evaluated with respect to the clinicoradiological parameters. Predictors of rapid tumor growth (defined as growth ≥ 2 cm3/yr) were analyzed using univariate followed by multivariate logistic regression to build a dedicated predicting model. Receiver operating characteristic (ROC) curves to predict the risk of rapid tumor growth with the AIMSS versus the authors' multivariate model were compared. RESULTS: Sixty tumors (16.76%) showed rapid growth. After multivariate analysis, a larger tumor volume at diagnosis (p < 0.0001), presence of peritumoral edema (p = 0.022), absence of calcifications (p < 0.0001), and hyperintense or isointense signal on T2-weighted MRI (p < 0.005) were statistically significantly associated with rapid tumor growth. It is particularly notable that the genetic severity score did not seem to influence the growth rate of NF2 meningiomas. In comparison with the AIMSS, the authors' multivariate model's prediction did not show a statistically significant difference (area under the curve [AUC] 0.82 [95% CI 0.76-0.88] for the AIMSS vs AUC 0.86 [95% CI 0.81-0.91] for the authors' model, p = 0.1). CONCLUSIONS: The AIMSS score is valid in the authors' cohort of NF2-related meningiomas. It adequately predicted risk of rapid meningioma growth and could aid in decision-making in NF2 patients.