Somatic mutations in endothelial cells and cerebral vascular malformations

doi:10.3969/j.issn.1006-7795.2024.03.002

Abstract

Abstract: Cerebral vascular malformations (CVMs) are non-neoplastic lesions of local brain vasculature in which the quantity and structure of cerebral vessels are altered due to genetic, cytokine, and protein changes caused by various intrinsic and extrinsic factors during embryonic development. Somatic mutations in endothelial cells, as one of the initiating factors, play a crucial role in the occurrence and development of CVMs. Understanding the endothelial cell mutations in CVMs is of great significance for preventing CVMs occurrence and development, developing targeted drugs, and guiding clinical treatment. This review focuses on the discovery, clinical relevance, and potential therapeutic implications of endothelial cell somatic mutations in CVMs.

Key words: cerebral vascular malformations, endothelial cell, somatic mutation, targeted therapy

CLC Number:

R743

Zhao Shaozhi, Cao Yong. Somatic mutations in endothelial cells and cerebral vascular malformations[J]. Journal of Capital Medical University, 2024, 45(3): 379-384.

References

［1］Toulgoat F, Lasjaunias P. Vascular malformations of the brain［J］. Handb Clin Neurol, 2013, 112: 1043－1051.
［2］Zafar A, Fiani B, Hadi H, et al. Cerebral vascular malformations and their imaging modalities［J］. Neurol Sci, 2020, 41(9):2407－2421.
［3］Brown R D Jr, Flemming K D, Meyer F B, et al. Natural history, evaluation, and management of intracranial vascular malformations［J］. Mayo Clin Proc, 2005, 80:269－281.
［4］Spetzler R F, Martin N A. A proposed grading system for arteriovenous malformations［J］. J Neurosurg, 1986, 65(4):476－483.
［5］Milholland B, Dong X, Zhang L, et al. Differences between germline and somatic mutation rates in humans and mice［J］. Nat Commun, 2017, 8:15183.
［6］Maury E A, Walsh C A, Kahle K T. Neurosurgery elucidates somatic mutations［J］. Science, 2023, 382(6677):1360－1362.
［7］Lawton M T, Rutledge W C, Kim H, et al. Brain arteriovenous malformations［J］. Nat Rev Dis Primers, 2015, 1:15008.
［8］Nikolaev S I, Vetiska S, Bonilla X, et al. Somatic activating KRAS mutations in arteriovenous malformations of the brain［J］. N Engl J Med, 2018, 378(3):250－261.
［9］Li H, Nam Y, Huo R, et al. De novo germline and somatic variants convergently promote endothelial-to-mesenchymal transition in simplex brain arteriovenous malformation［J］. Circ Res, 2021, 129:825－839.
［10］Hong T, Yan Y P, Li J W, et al. High prevalence of KRAS/BRAF somatic mutations in brain and spinal cord arteriovenous malformations［J］. Brain, 2019, 142(1):23－34.
［11］Xu H Y, Huo R, Li H, et al. KRAS mutation-induced EndMT of brain arteriovenous malformation is mediated through the TGF-β/BMP-SMAD4 pathway［J］. Stroke Vasc Neurol, 2023, 8(3):197－206.
［12］He Q H, Huo R, Wang J, et al. Exosomal miR-3131 derived from endothelial cells with KRAS mutation promotes EndMT by targeting PICK1 in brain arteriovenous malformations［J］. CNS Neurosci Ther, 2023, 29(5):1312－1324.
［13］Al-Holou W N, O′Lynnger T M, Pandey A S, et al. Natural history and imaging prevalence of cavernous malformations in children and young adults［J］. J Neurosurg Pediatr, 2012, 9(2):198－205.
［14］Chohan M O, Marchiò S, Morrison L A, et al. Emerging pharmacologic targets in cerebral cavernous malformation and potential strategies to alter the natural history of a difficult disease: a review［J］. JAMA Neurol, 2019, 76(4):492－500.
［15］Riant F, Bergametti F, Ayrignac X, et al. Recent insights into cerebral cavernous malformations: the molecular genetics of CCM［J］. FEBS J, 2010, 277(5):1070－1075.
［16］Akers A, Al-Shahi Salman R, A Awad I, et al. Synopsis of guidelines for the clinical management of cerebral cavernous malformations: consensus recommendations based on systematic literature review by the angioma alliance scientific advisory board clinical experts panel［J］. Neurosurgery, 2017, 80(5):665－680.
［17］Sahoo T, Johnson E W, Thomas J W, et al. Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1)［J］. Hum Mol Genet, 1999, 8(12):2325－2333.
［18］Laberge-le Couteulx S, Jung H H, Labauge P, et al. Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas［J］. Nat Genet, 1999, 23(2):189－193.
［19］Denier C, Goutagny S, Labauge P, et al. Mutations within the MGC4607 gene cause cerebral cavernous malformations［J］. Am J Hum Genet, 2004, 74(2):326－337.
［20］Liquori C L, Berg M J, Siegel A M, et al. Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations［J］. Am J Hum Genet, 2003, 73(6): 1459－1464.
［21］Bergametti F, Denier C, Labauge P, et al. Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations［J］. Am J Hum Genet, 2005, 76(1):42－51.
［22］Snellings D A, Hong C C, Ren A A, et al. Cerebral cavernous malformation: from mechanism to therapy［J］. Circ Res, 2021, 129(1):195－215.
［23］Gault J, Shenkar R, Recksiek P, et al. Biallelic somatic and germ line CCM1 truncating mutations in a cerebral cavernous malformation lesion［J］. Stroke, 2005, 36(4):872－874.
［24］Gault J, Awad I A, Recksiek P, et al. Cerebral cavernous malformations: somatic mutations in vascular endothelial cells［J］. Neurosurgery, 2009, 65(1):138－144.
［25］McDonald D A, Shi C B, Shenkar R, et al. Lesions from patients with sporadic cerebral cavernous malformations harbor somatic mutations in the CCM genes: evidence for a common biochemical pathway for CCM pathogenesis［J］. Hum Mol Genet, 2014, 23(16):4357－4370.
［26］Ren A A, Snellings D A, Su Y S, et al. PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism［J］. Nature, 2021, 594(7862):271－276.
［27］Weng J C, Yang Y X, Song D, et al. Somatic MAP3K3 mutation defines a subclass of cerebral cavernous malformation［J］. Am J Hum Genet, 2021, 108(5):942－950.
［28］Hong T, Xiao X, Ren J, et al. Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations［J］. Brain, 2021, 144(9):2648－2658.
［29］Ressler A K, Snellings D A, Girard R, et al. Single-nucleus DNA sequencing reveals hidden somatic loss-of-heterozygosity in cerebral cavernous malformations［J］. Nat Commun, 2023, 14(1):7009.
［30］Huo R, Yang Y X, Sun Y F, et al. Endothelial hyperactivation of mutant MAP3K3 induces cerebral cavernous malformation enhanced by PIK3CA GOF mutation［J］. Angiogenesis, 2023, 26(2):295－312.
［31］Naik S, Phadke R V, Taunk A, et al. Dynamic contrast-enhanced magnetic resonance imaging in diagnosis of cavernous hemangioma of cavernous sinus［J］. J Neurosci Rural Pract, 2017, 8(2):311－313.
［32］Linskey M E, Sekhar L N. Cavernous sinus hemangiomas: a series, a review, and an hypothesis［J］. Neurosurgery, 1992, 30(1):101－108.
［33］Huo R, Yang Y X, Xu H Y, et al. Somatic GJA4 mutation in intracranial extra-axial cavernous hemangiomas［J］. Stroke Vasc Neurol, 2023, 8(6):453－462.
［34］Wang J, Tang J H, Yang Y X, et al. Genotype-phenotype correlations in multiple lesions of familial cerebral cavernous malformations concerning phosphatidylinositol 3-kinase catalytic subunit alpha mutations［J］. Clin Transl Med, 2024, 14(3):e1610.
［35］Fu W L, Huo R, Yan Z H, et al. Mesenchymal behavior of the endothelium promoted by SMAD6 downregulation is associated with brain arteriovenous malformation microhemorrhage［J］. Stroke, 2020, 51(7):2197－2207.
［36］Pawlikowska L, Tran M N, Achrol A S, et al. Polymorphisms in genes involved in inflammatory and angiogenic pathways and the risk of hemorrhagic presentation of brain arteriovenous malformations［J］. Stroke, 2004, 35(10):2294－2300.
［37］Achrol A S, Pawlikowska L, McCulloch C E, et al. Tumor necrosis factor-alpha-238G>A promoter polymorphism is associated with increased risk of new hemorrhage in the natural course of patients with brain arteriovenous malformations［J］. Stroke, 2006, 37(1):231－234.
［38］Pawlikowska L, Tran M N, Achrol A S, et al. Polymorphisms in transforming growth factor-beta-related genes ALK1 and ENG are associated with sporadic brain arteriovenous malformations［J］. Stroke, 2005, 36(10):2278－2280.
［39］Hartmann K, Sadée C Y, Satwah I, et al. Imaging genomics: data fusion in uncovering disease heritability［J］. Trends Mol Med, 2023, 29(2):141－151.
［40］Zabramski J M, Wascher T M, Spetzler R F, et al. The natural history of familial cavernous malformations: results of an ongoing study［J］. J Neurosurg, 1994, 80(3):422－432.
［41］Zhou L F, Mao Y, Chen L. Diagnosis and surgical treatment of cavernous sinus hemangiomas: an experience of 20 cases［J］. Surg Neurol, 2003, 60(1):31－36.
［42］Shi J, Hang C, Pan Y, et al. Cavernous hemangiomas in the cavernous sinus［J］. Neurosurgery, 1999, 45(6):1308－1313.

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