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

Peyre, Matthieu; Miyagishima, Danielle F; Bielle, Franck; Chapon, Françoise; Sierant, Michael C.; Venot, Quitterie; Lerond, Julie; Marijon, Pauline; Abi-Jaoude, Samiya; Van, Tuan Le; Labreche, Karim; Houlston, Richard S.; Faisant, Maxime; Clemenceau, Stéphane; Boch, Anne‐Laure; Nouet, Aurélien; Carpentier, Alexandre; Boetto, Julien; Louvi, Angeliki; Kalamaridès, Michel

doi:10.1056/nejmoa2100440

Cited by 65 publications

(52 citation statements)

References 44 publications

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“…Another important observation of our model is that Pik3ca ‐related blood vascular malformations only occur in veins and in the capillary bed, excluding arteries which remain unaltered. This resembles the human spectrum of vascular malformations where PIK3CA mutations have not been reported in arterial malformations (Peyre et al , 2021 ; Ren et al , 2021 ). Why arteries are unaffected by Pik3ca mutation remains unclear.…”

Section: Discussionsupporting

confidence: 61%

The onset of PI3K‐related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib

et al. 2022

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Low-flow vascular malformations are congenital overgrowths composed of abnormal blood vessels potentially causing pain, bleeding and obstruction of different organs. These diseases are caused by oncogenic mutations in the endothelium, which result in overactivation of the PI3K/AKT pathway. Lack of robust in vivo preclinical data has prevented the development and translation into clinical trials of specific molecular therapies for these diseases. Here, we demonstrate that the Pik3ca H1047R activating mutation in endothelial cells triggers a transcriptome rewiring that leads to enhanced cell proliferation. We describe a new reproducible preclinical in vivo model of PI3K-driven vascular malformations using the postnatal mouse retina. We show that active angiogenesis is required for the pathogenesis of vascular malformations caused by activating Pik3ca mutations. Using this model, we demonstrate that the AKT inhibitor miransertib both prevents and induces the regression of PI3K-driven vascular malformations. We confirmed the efficacy of miransertib in isolated human endothelial cells with genotypes spanning most of human lowflow vascular malformations.

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Section: Discussionsupporting

confidence: 61%

The onset of PI3K‐related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib

et al. 2022

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“…In particular, despite the shortcoming of a low number of patients analyzed, our identification of NOTCH3 and PTEN variants in CCM cases raises the possibility that the somatic mosaicism of either NOTCH3 or PTEN mutations and their impact on redox mechanisms and oxy-inflammatory responses contribute to CCM disease pathogenesis and severity, thereby supporting the necessity for implemented NGS analysis to enable the sensitive identification of causal genetic variants and effective polygenic risk prediction. In turn, the possibility that both NOTCH3 and PTEN variants contribute to CCM disease pathogenesis and severity is consistent with the recent discovery that NOTCH3 can transactivate PTEN and inhibit the PTEN downstream Akt/mTOR pathway [97], and the parallel identification of CCM causative mutations in genes involved in such a pathway, including PIK3CA and Akt [14][15][16]. Further analyses in experimental models and large patient cohorts are needed to address the new research perspectives and challenges evoked by our study, including the necessity to combine the identification of potentially significant variants in both causative and modifier genes underlying the broad variability of CCM phenotypes in order to allow effective polygenic risk stratification and personalized treatment for CCM disease.…”

Section: Discussionsupporting

confidence: 78%

Next-Generation Sequencing Advances the Genetic Diagnosis of Cerebral Cavernous Malformation (CCM)

et al. 2022

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Cerebral Cavernous Malformation (CCM) is a cerebrovascular disease of genetic origin that predisposes to seizures, focal neurological deficits and fatal intracerebral hemorrhage. It may occur sporadically or in familial forms, segregating as an autosomal dominant condition with incomplete penetrance and highly variable expressivity. Its pathogenesis has been associated with loss-of-function mutations in three genes, namely KRIT1 (CCM1), CCM2 and PDCD10 (CCM3), which are implicated in defense mechanisms against oxidative stress and inflammation. Herein, we screened 21 Italian CCM cases using clinical exome sequencing and found six cases (~29%) with pathogenic variants in CCM genes, including a large 145–256 kb genomic deletion spanning the KRIT1 gene and flanking regions, and the KRIT1 c.1664C>T variant, which we demonstrated to activate a donor splice site in exon 16. The segregation of this cryptic splicing mutation was studied in a large Italian family (five affected and seven unaffected cases), and showed a largely heterogeneous clinical presentation, suggesting the implication of genetic modifiers. Moreover, by extending genetic analysis to a virtual panel of 23 cerebrovascular disease-related genes (Cerebro panel), we found two variants in NOTCH3 and PTEN genes, which could contribute to the abnormal oxidative stress and inflammatory responses to date implicated in CCM disease pathogenesis.

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“…Moreover, lesions resembling cavernomas arise after CCM inactivation neural progenitor cells 43 or vascular pericytes. 44,45 We have obtained cavernomas and induced the Klf transcription factors by disrupting Stk24 and Stk25 together. These 2 kinases have also recently been shown to have overlapping activities in neuronal migration 46 and kidney water reabsorption.…”

Section: Discussionmentioning

confidence: 99%

GCKIII (Germinal Center Kinase III) Kinases STK24 and STK25 (Serine/Threonine Kinase 24 and 25) Inhibit Cavernoma Development

Sartages

García-Colomer

Iglesias

et al. 2022

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Background: Cavernous cerebral malformations can arise because of mutations in the CCM1 , CCM2 , or CCM3 genes, and lack of Cdc42 has also been reported to induce these malformations in mice. However, the role of the CCM3 (cerebral cavernous malformation 3)-associated kinases in cavernoma development is not known, and we, therefore, have investigated their role in the process. Methods: We used a combination of an in vivo approach, using mice genetically modified to be deficient in the CCM3-associated kinases STK24 and STK25 (serine/threonine kinases 24 and 25), and the in vitro model of human endothelial cells in which expression of STK24 and STK25 was inhibited by RNA interference. Results: Mice deficient for both Stk24 and Stk25 , but not for either of them individually, developed aggressive vascular lesions with the characteristics of cavernomas at an early age. Stk25 deficiency also gave rise to vascular anomalies in the context of Stk24 heterozygosity. Human endothelial cells deficient for both kinases phenocopied several of the consequences of CCM3 loss, and single STK25 deficiency also induced KLF2 expression, Golgi dispersion, altered distribution of β-catenin, and appearance of stress fibers. Conclusions: The CCM3-associated kinases STK24 and STK25 play a major role in the inhibition of cavernoma development.

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SomaticPIK3CAMutations in Sporadic Cerebral Cavernous Malformations

Cited by 65 publications

References 44 publications

The onset of PI3K‐related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib

The onset of PI3K‐related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib

Next-Generation Sequencing Advances the Genetic Diagnosis of Cerebral Cavernous Malformation (CCM)

GCKIII (Germinal Center Kinase III) Kinases STK24 and STK25 (Serine/Threonine Kinase 24 and 25) Inhibit Cavernoma Development

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