Dataset Information

Somatic PIK3CA Mutations in Sporadic Cerebral Cavernous Malformations.

ABSTRACT:

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.).

SUBMITTER: Peyre M

PROVIDER: S-EPMC8606022 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Publications

Somatic <i>PIK3CA</i> Mutations in Sporadic Cerebral Cavernous Malformations.

Peyre Matthieu M Miyagishima Danielle D Bielle Franck F Chapon Françoise F Sierant Michael M Venot Quitterie Q Lerond Julie J Marijon Pauline P Abi-Jaoude Samiya S Le Van Tuan T Labreche Karim K Houlston Richard R Faisant Maxime M Clémenceau Stéphane S Boch Anne-Laure AL Nouet Aurelien A Carpentier Alexandre A Boetto Julien J Louvi Angeliki A Kalamarides Michel M

The New England journal of medicine 20210901 11

<h4>Background</h4>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 <i>KRIT1</i> (<i>CCM1</i>), <i>CCM2</i>, or <i>PDCD10</i> (<i>CCM3</i>), the genetic cause of sporadic CCMs, representing 80% of cases, remains incompletely understood.<h4>Methods</h4>We developed two mouse models harboring mutations identified in human meningiomas with the use of the ...[more]

PMID: 34496175

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Project description:Cerebral cavernous malformations (CCM) are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and focal neurological deficits due to cerebral hemorrhages. CCM loci have already been assigned to chromosomes 7q (CCM1), 7p (CCM2), and 3q (CCM3) and have been identified in 40%, 20%, and 40%, respectively, of families with CCM. Loss-of-function mutations have been identified in CCM1/KRIT1, the sole CCM gene identified to date. We report here the identification of MGC4607 as the CCM2 gene. We first reduced the size of the CCM2 interval from 22 cM to 7.5 cM by genetic linkage analysis. We then hypothesized that large deletions might be involved in the disorder, as already reported in other hamartomatous conditions, such as tuberous sclerosis or neurofibromatosis. We performed a high-density microsatellite genotyping of this 7.5-cM interval to search for putative null alleles in 30 unrelated families, and we identified, in 2 unrelated families, null alleles that were the result of deletions within a 350-kb interval flanked by markers D7S478 and D7S621. Additional microsatellite and single-nucleotide polymorphism genotyping showed that these two distinct deletions overlapped and that both of the two deleted the first exon of MGC4607, a known gene of unknown function. In both families, one of the two MGC4607 transcripts was not detected. We then identified eight additional point mutations within MGC4607 in eight of the remaining families. One of them led to the alteration of the initiation codon and five of them to a premature termination codon, including one nonsense, one frameshift, and three splice-site mutations. All these mutations cosegregated with the disease in the families and were not observed in 192 control chromosomes. MGC4607 is so far unrelated to any known gene family. Its implication in CCMs strongly suggests that it is a new player in vascular morphogenesis.