ArticleHuman molecular genetics2014
Lesions from patients with sporadic cerebral cavernous malformations harbor somatic mutations in the CCM genes: evidence for a common biochemical pathway for CCM pathogenesis.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers, 1 of them a synthesis that pooled it.
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Who cites it
80 citing papers in PubMed, 1 synthesis or guideline pooled it, 139 citations in OpenAlex.
- Pooled it
- Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial.Neurosurgery · 2019Trial
- Familial Cerebral Cavernous Malformations: Pathophysiology, Genetics, Biomarkers, and Treatment Perspectives.Journal of neurochemistry · 2026Review
- Late-onset familial cerebral cavernous malformation without a family history: a case description.Quantitative imaging in medicine and surgery · 2025Article
- High-throughput differentiation of human blood vessel organoids reveals overlapping and distinct functions of the cerebral cavernous malformation proteins.Angiogenesis · 2025Article
- Review
- Epidemiology and Aetiology of Cerebral Cavernous Malformations.Acta neurochirurgica. Supplement · 2025Review
- Cerebral Cavernous Malformation: From Genetics to Pharmacotherapy.Brain and behavior · 2025Review
- Review
- Somatic mutations in arteriovenous malformations in hereditary hemorrhagic telangiectasia support a bi-allelic two-hit mutation mechanism of pathogenesis.American journal of human genetics · 2024Article
- Transcriptomic signatures of individual cell types in cerebral cavernous malformation.Cell communication and signaling : CCS · 2024Article
- mTORC1 Inhibitor Rapamycin Inhibits Growth of Cerebral Cavernous Malformation in Adult Mice.Stroke · 2023Article
- Magnetic Resonance Imaging of Mouse Cerebral Cavernomas Reveal Differential Lesion Progression and Variable Permeability to Gadolinium.Arteriosclerosis, thrombosis, and vascular biology · 2023Article
- Endothelial hyperactivation of mutant MAP3K3 induces cerebral cavernous malformation enhanced by PIK3CA GOF mutation.Angiogenesis · 2023Article
- Plasma metabolites with mechanistic and clinical links to the neurovascular disease cavernous angioma.Communications medicine · 2023Article
- Endothelial Differentiation ofInternational journal of molecular sciences · 2023Article
- A feasibility study for quantitative assessment of cerebrovascular malformations using flutriciclamide ([Frontiers in medicine · 2023Article
- Variable histopathology features of neuronal dyslamination in the cerebral neocortex adjacent to epilepsy-associated vascular malformations suggest complex pathogenesis of focal cortical dysplasia ILAE type IIIc.Brain pathology (Zurich, Switzerland) · 2022Review
- Contact-dependent signaling triggers tumor-like proliferation of CCM3 knockout endothelial cells in co-culture with wild-type cells.Cellular and molecular life sciences : CMLS · 2022Article
- Rapamycin in Cerebral Cavernous Malformations: What Doses to Test in Mice and Humans.ACS pharmacology & translational science · 2022Review
20 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 5 institutions in 1 country.
Funding
Abstract
Cerebral cavernous malformations (CCMs) are vascular lesions affecting the central nervous system. CCM occurs either sporadically or in an inherited, autosomal dominant manner. Constitutional (germline) mutations in any of three genes, KRIT1, CCM2 and PDCD10, can cause the inherited form. Analysis of CCM lesions from inherited cases revealed biallelic somatic mutations, indicating that CCM follows a Knudsonian two-hit mutation mechanism. It is still unknown, however, if the sporadic cases of CCM also follow this genetic mechanism. We extracted DNA from 11 surgically excised lesions from sporadic CCM patients, and sequenced the three CCM genes in each specimen using a next-generation sequencing approach. Four sporadic CCM lesion samples (36%) were found to contain novel somatic mutations. Three of the lesions contained a single somatic mutation, and one lesion contained two biallelic somatic mutations. Herein, we also describe evidence of somatic mosaicism in a patient presenting with over 130 CCM lesions localized to one hemisphere of the brain. Finally, in a lesion regrowth sample, we found that the regrown CCM lesion contained the same somatic mutation as the original lesion. Together, these data bolster the idea that all forms of CCM have a genetic underpinning of the two-hit mutation mechanism in the known CCM genes. Recent studies have found aberrant Rho kinase activation in inherited CCM pathogenesis, and we present evidence that this pathway is activated in sporadic CCM patients. These results suggest that all CCM patients, including those with the more common sporadic form, are potentially amenable to the same therapy.
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