• Matthieu Peyre, Danielle Miyagishima, Franck Bielle, Françoise Chapon, Michael Sierant, Quitterie Venot, Julie Lerond, Pauline Marijon, Samiya Abi-Jaoude, Tuan Le Van, Karim Labreche, Richard Houlston, Maxime Faisant, Stéphane Clémenceau, Anne-Laure Boch, Aurelien Nouet, Alexandre Carpentier, Julien Boetto, Angeliki Louvi, and Michel Kalamarides.
• From the Departments of Neurosurgery (M.P., S.C., A.-L.B., A.N., A.C., M.K.) and Neuropathology (F.B.), Sorbonne Université, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, INSERM Unité 1127, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, Paris Brain Institute (M.P., F.B., J.L., P.M., S.A.-J., T.L.V., K.L., J.B., M.K.), and INSERM Unité 1151-Institut Necker Enfants Malades, Hôpital Necker Enfants Malades, AP-HP (Q.V.), Paris, and the Department of Pathology, Centre Hospitalier Régional Universitaire (CHRU) Caen-INSERM Unité 1075 COMETE, Caen University (F.C.), and the Department of Pathology CHRU Caen-INSERM Unité Mixte de Recherche en Santé Unité 1237, Cyceron (M.F.), Caen - all in France; the Departments of Genetics (D.M., M.S.) and Neurosurgery and Neuroscience (A.L.), Yale School of Medicine, New Haven, CT; and the Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, United Kingdom (K.L., R.H.).
• N. Engl. J. Med. 2021 Sep 9; 385 (11): 996-1004.

BackgroundCerebral 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.MethodsWe 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.ResultsWe 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.ConclusionsIn 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.).Copyright © 2021 Massachusetts Medical Society.

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