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dc.contributor.authorPeyre, M
dc.contributor.authorMiyagishima, D
dc.contributor.authorBielle, F
dc.contributor.authorChapon, F
dc.contributor.authorSierant, M
dc.contributor.authorVenot, Q
dc.contributor.authorLerond, J
dc.contributor.authorMarijon, P
dc.contributor.authorAbi-Jaoude, S
dc.contributor.authorLe Van, T
dc.contributor.authorLabreche, K
dc.contributor.authorHoulston, R
dc.contributor.authorFaisant, M
dc.contributor.authorClémenceau, S
dc.contributor.authorBoch, A-L
dc.contributor.authorNouet, A
dc.contributor.authorCarpentier, A
dc.contributor.authorBoetto, J
dc.contributor.authorLouvi, A
dc.contributor.authorKalamarides, M
dc.date.accessioned2021-12-07T14:56:16Z
dc.date.available2021-12-07T14:56:16Z
dc.identifier.citationThe New England journal of medicine, 2021, 385 (11), pp. 996 - ?
dc.identifier.issn0028-4793
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4915
dc.identifier.eissn1533-4406
dc.identifier.doi10.1056/nejmoa2100440
dc.description.abstractBackground 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.).
dc.formatPrint
dc.format.extent996 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectAnimals
dc.subjectMice, Inbred Strains
dc.subjectHumans
dc.subjectMice
dc.subjectMeningioma
dc.subjectIntracranial Arteriovenous Malformations
dc.subjectDisease Models, Animal
dc.subjectMutation
dc.subjectFemale
dc.subjectMale
dc.subjectProto-Oncogene Proteins c-akt
dc.subjectClass I Phosphatidylinositol 3-Kinases
dc.subjectKRIT1 Protein
dc.titleSomatic <i>PIK3CA</i> Mutations in Sporadic Cerebral Cavernous Malformations.
dc.typeJournal Article
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1056/nejmoa2100440
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2021-09-01
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfThe New England journal of medicine
pubs.issue11
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Cancer Genomics
pubs.publication-statusPublished
pubs.volume385
pubs.embargo.termsNot known
icr.researchteamCancer Genomics
dc.contributor.icrauthorHoulston, Richarden_US


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