Endothelial hyperactivation of mutant MAP3K3 induces cerebral cavernous malformation enhanced by PIK3CA GOF mutation

Huo, Ran; Yang, Yingxi; Sun, Yingfan; Zhou, Qiuxia; Zhao, Shufang; Mo, Zongchao; Xu, Hongyuan; Wang, Jie; Weng, Jian-Cong; Jiao, Yuming; Zhang, Junze; He, Qiheng; Wang, Shuo; Zhao, Jizong; Wang, Ji‐Guang; Cao, Yong

doi:10.1007/s10456-023-09866-9

Cited by 7 publications

(5 citation statements)

References 42 publications

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“…Because the total DNA extracted from FFPE samples was limited, ddPCR was applied to detect the prevalent PIK3CA mutations. 5 PIK3CA mutations were found in 10 samples (Figure 2A,B, Figures S2-S6 and Table S3). Overall, 86.7% (13/15) ICH lesions harboured somatic PIK3CA plus CCM germline mutations, whereas 100% (3/3) dot-sized lesions had only CCM germline mutations (p = 0.012) (Figure 2C, Figure S2-S6 and Table S3).…”

Section: Genotype-phenotype Correlations In Multiple Lesions Of Famil...mentioning

confidence: 99%

“…In familiar cases, CCM germline mutations occur earlier than somatic PIK3CA mutations, nevertheless, CCM mutations may be a secondary event following the mutation of PI3K pathway genes in sporadic cases. [3][4][5] Two subgroups' lesions harboured different genotypes and related phenotypes, which implies an underlying molecular mechanism within them. Recent studies indicated that PIK3CA mutation was associated with haemorrhagic events in CCMs.…”

Section: Genotype-phenotype Correlations In Multiple Lesions Of Famil...mentioning

confidence: 99%

“…Jie Wang 1,2 Jihong Tang 3,4 Yingxi Yang 4 Yuming Jiao 1,2 Ran Huo 1,2 Hongyuan Xu 1,2 Shaozhi Zhao 1,2 Yingfan Sun 1,2 Qiheng He 1,2 Qifeng Yu 1,2 Shuo Wang 1,2 Jizong Zhao 1,2 Jiguang Wang 3,4,5 Yong Cao…”

Section: A U T H O R C O N T R I B U T I O N Sunclassified

mentioning

confidence: 99%

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Genotype‐phenotype correlations in multiple lesions of familial cerebral cavernous malformations concerning phosphatidylinositol 3‐kinase catalytic subunit alpha mutations

Wang,

Tang,

Yang

et al. 2024

Clinical & Translational Med

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Section: Genotype-phenotype Correlations In Multiple Lesions Of Famil...mentioning

confidence: 99%

Section: Genotype-phenotype Correlations In Multiple Lesions Of Famil...mentioning

confidence: 99%

Section: A U T H O R C O N T R I B U T I O N Sunclassified

mentioning

confidence: 99%

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Genotype‐phenotype correlations in multiple lesions of familial cerebral cavernous malformations concerning phosphatidylinositol 3‐kinase catalytic subunit alpha mutations

Wang,

Tang,

Yang

et al. 2024

Clinical & Translational Med

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“…In sporadic nonfamilial forms of CCM, CCM LOF or MAP3K3 GOF mutations were frequently found together with PIK3CA GOF mutations ( 134 ). Particularly aggressive forms of CCMs arise when both oncogenic Map3k3 and Pik3ca GOF mutations co-occur within the affected murine endothelium ( 135 ). In CCM disease animal models and human CCM protein-deficient ECs, oncogenic Pik3ca H1047R mutations synergized with loss of CCM proteins and strongly aggravated lesion formation ( 24 ).…”

Section: Genetic Third Hits Involving Pik3ca In Ccmsmentioning

confidence: 99%

Shear stress and pathophysiological PI3K involvement in vascular malformations

Abdelilah-Seyfried,

Ola

2024

Journal of Clinical Investigation

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Molecular characterization of vascular anomalies has revealed that affected endothelial cells (ECs) harbor gain-of-function (GOF) mutations in the gene encoding the catalytic α subunit of PI3Kα ( PIK3CA ). These PIK3CA mutations are known to cause solid cancers when occurring in other tissues. PIK3CA -related vascular anomalies, or “PIKopathies,” range from simple, i.e., restricted to a particular form of malformation, to complex, i.e., presenting with a range of hyperplasia phenotypes, including the PIK3CA -related overgrowth spectrum. Interestingly, development of PIKopathies is affected by fluid shear stress (FSS), a physiological stimulus caused by blood or lymph flow. These findings implicate PI3K in mediating physiological EC responses to FSS conditions characteristic of lymphatic and capillary vessel beds. Consistent with this hypothesis, increased PI3K signaling also contributes to cerebral cavernous malformations, a vascular disorder that affects low-perfused brain venous capillaries. Because the GOF activity of PI3K and its signaling partners are excellent drug targets, understanding PIK3CA ’s role in the development of vascular anomalies may inform therapeutic strategies to normalize EC responses in the diseased state. This Review focuses on PIK3CA ’s role in mediating EC responses to FSS and discusses current understanding of PIK3CA dysregulation in a range of vascular anomalies that particularly affect low-perfused regions of the vasculature. We also discuss recent surprising findings linking increased PI3K signaling to fast-flow arteriovenous malformations in hereditary hemorrhagic telangiectasias.

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Understanding the pathogenesis of brain arteriovenous malformation: genetic variations, epigenetics, signaling pathways, and immune inflammation

Wang,

Deng,

et al. 2023

Hum. Genet.

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Endothelial hyperactivation of mutant MAP3K3 induces cerebral cavernous malformation enhanced by PIK3CA GOF mutation

Cited by 7 publications

References 42 publications

Genotype‐phenotype correlations in multiple lesions of familial cerebral cavernous malformations concerning phosphatidylinositol 3‐kinase catalytic subunit alpha mutations

Genotype‐phenotype correlations in multiple lesions of familial cerebral cavernous malformations concerning phosphatidylinositol 3‐kinase catalytic subunit alpha mutations

Shear stress and pathophysiological PI3K involvement in vascular malformations

Understanding the pathogenesis of brain arteriovenous malformation: genetic variations, epigenetics, signaling pathways, and immune inflammation

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