PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism

Ren, Aileen; Snellings, Daniel A.; Su, YouRong Sophie; Hong, Courtney C.; Castro, Marco; Tang, Alan T.; Detter, Matthew R; Hobson, Nicholas; Girard, Romuald; Romanos, Sharbel; Lightle, Rhonda; Moore, Thomas; Shenkar, Robert; Benavides, Christian R; Beaman, M. Makenzie; Müller-Fielitz, Helge; Chen, Mei; Mericko, Patricia; Yang, Jun; Sung, Derek C.; Lawton, Michael T.; Ruppert, J. Michael; Schwaninger, Markus; Körbelin, Jakob; Potente, Michael; Awad, Issam A.; Marchuk, Douglas A.; Kahn, Mark L.

doi:10.1038/s41586-021-03562-8

Cited by 136 publications

(170 citation statements)

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“…While somatic mutations in KRIT1, CCM2, PDCD10, and MAP3K3 are mutually exclusive, somatic gain of function mutations in PIK3CA may co-occur with any other mutation (Figure 1A). We have previously shown that co-occurring mutations in KRIT1/CCM2 and PIK3CA occur in the same clonal population of cells 10 . To determine whether MAP3K3 and PIK3CA mutations co-exist in the same cells we performed single-nucleus DNA-sequencing (snDNA-seq) on frozen tissue from three surgically resected CCMs determined to harbor both mutations (Figure 1B-D).…”

Section: Resultsmentioning

confidence: 98%

“…To evaluate whether sporadic and familial CCMs have distinct somatic mutation spectra we identified somatic mutations present in 71 CCMs (20 familial CCMs and 51 sporadic/presumed sporadic CCMs). Mutations in KRIT1, CCM2, PDCD10, and PIK3CA were detected by targeted sequencing and/or droplet digital PCR (ddPCR) as previously described 10 . The common gain of function mutation in MAP3K3 (hg38 chr17:63691212, NM 002401.3, c.1323C>G; NP 002392, p.I441M) was detected by ddPCR using a previously published probe set 20 .…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have established that CCM pathogenesis follows a genetic two-hit model where somatic mutations cause biallelic LOF in KRIT1, CCM2, or PDCD10 to initiate lesion formation [5][6][7][8] . Recent studies have found that somatic mutations in PIK3CA and MAP3K3 also contribute to CCM pathogenesis [9][10][11] . These discoveries opened new avenues for research and therapeutic development, but they also raised new questions about the roles of somatic mutations in familial versus sporadic lesions.…”

Section: Introductionmentioning

confidence: 99%

“…CCMs have long been known to follow a genetic two-hit model where lesion formation is initiated by somatic mutations resulting in biallelic loss of a CCM complex gene [5][6][7][8] . Recent studies have shown that somatic mutations in MAP3K3 and PIK3CA also contribute to CCM pathogenesis [9][10][11] ; however, it remains unclear how these mutations contribute to sporadic versus familial cases. Here we show that somatic mutations in MAP3K3 are mutually exclusive with mutations in CCM complex genes and that mutations in MAP3K3 contribute to sporadic, but not familial CCM.…”

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confidence: 99%

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Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations

Snellings

Girard

Lightle

et al. 2021

Preprint

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Cerebral cavernous malformations (CCM) are a neurovascular anomaly that may occur sporadically in otherwise healthy individuals, or be inherited by autosomal dominant mutations in the genes that encode the proteins of the CCM signaling complex (KRIT1, CCM2, or PDCD10). CCMs have long been known to follow a genetic two-hit model where lesion formation is initiated by somatic mutations resulting in biallelic loss of a CCM complex gene. Recent studies have shown that somatic mutations in MAP3K3 and PIK3CA also contribute to CCM pathogenesis; however, it remains unclear how these mutations contribute to sporadic versus familial cases. Here we show that somatic mutations in MAP3K3 are mutually exclusive with mutations in CCM complex genes and that mutations in MAP3K3 contribute to sporadic, but not familial CCM. Using single-nucleus DNA sequencing, we show that co-occurring MAP3K3 and PIK3CA mutations are present within the same clonal population of cells. Furthermore, we identify PIK3CA mutations in CCM-associated developmental venous anomalies (DVA). It has long been known that sporadic CCM often develop in the vicinity of a DVA. However, the underlying cause of this association is unknown. In this first report of the molecular pathology of CCM-associated DVA, we find that the identical PIKC3A mutation is found in both the DVA and its associated CCM, but that an activating MAP3K3 mutation appears only in the CCM. These results support a mechanism where DVA develop as the result of a PIK3CA mutation, creating a region of the brain vasculature that functions as a genetic primer for CCM development following acquisition of an additional somatic mutation.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations

Snellings

Girard

Lightle

et al. 2021

Preprint

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“…Since the first reports of disease-causing CCM1 variants in familial CCM cases (Laberge-le Couteulx et al, 1999;Sahoo et al, 1999), we have learned a lot about CCM pathogenesis and the endothelial dysfunction in cavernous lesions (Maddaluno et al, 2013;Cuttano et al, 2016;Zhou et al, 2016;Detter et al, 2018;Malinverno et al, 2019;Hong et al, 2020;Ren et al, 2021). A first expert consensus guideline and clinical recommendations for CCM management have been published in recent years (Akers et al, 2017;Flemming and Lanzino, 2020).…”

Section: Introductionmentioning

confidence: 99%

Inactivation of Cerebral Cavernous Malformation Genes Results in Accumulation of von Willebrand Factor and Redistribution of Weibel-Palade Bodies in Endothelial Cells

Much

Sendtner

Schwefel

et al. 2021

Front. Mol. Biosci.

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Cerebral cavernous malformations are slow-flow thrombi-containing vessels induced by two-step inactivation of the CCM1, CCM2 or CCM3 gene within endothelial cells. They predispose to intracerebral bleedings and focal neurological deficits. Our understanding of the cellular and molecular mechanisms that trigger endothelial dysfunction in cavernous malformations is still incomplete. To model both, hereditary and sporadic CCM disease, blood outgrowth endothelial cells (BOECs) with a heterozygous CCM1 germline mutation and immortalized wild-type human umbilical vein endothelial cells were subjected to CRISPR/Cas9-mediated CCM1 gene disruption. CCM1−/− BOECs demonstrated alterations in cell morphology, actin cytoskeleton dynamics, tube formation, and expression of the transcription factors KLF2 and KLF4. Furthermore, high VWF immunoreactivity was observed in CCM1−/− BOECs, in immortalized umbilical vein endothelial cells upon CRISPR/Cas9-induced inactivation of either CCM1, CCM2 or CCM3 as well as in CCM tissue samples of familial cases. Observer-independent high-content imaging revealed a striking reduction of perinuclear Weibel-Palade bodies in unstimulated CCM1−/− BOECs which was observed in CCM1+/− BOECs only after stimulation with PMA or histamine. Our results demonstrate that CRISPR/Cas9 genome editing is a powerful tool to model different aspects of CCM disease in vitro and that CCM1 inactivation induces high-level expression of VWF and redistribution of Weibel-Palade bodies within endothelial cells.

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Intracranial venous malformation masquerading as a meningioma in PI3KCA‐related overgrowth spectrum disorder

Filippidis

Lidov

Al‐Ibraheemi

et al. 2021

American J of Med Genetics Pt A

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Gain of function PIK3CA pathogenic variants have been identified in overgrowth syndromes collectively termed "PIK3CA-related overgrowth spectrum" (PROS). There are no previously reported cases of cerebrovascular venous malformations in PROS syndromes, though somatic activating PIK3CA variants have been identified in extracranial venous malformation. This study was approved by the Institutional Review Boar at Boston Children's Hospital. A 14-year-old female mosaic for the de novo p.R108H pathogenic variant in the PIK3CA gene was found to have a large tumor involving the superior sagittal sinus with mass effect on the motor cortex most consistent with a parafalcine meningioma. She underwent surgical resection with pathology demonstrating a venous malformation. PIK3CA pathogenic variants have been

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PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism

Cited by 136 publications

References 51 publications

Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations

Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations

Inactivation of Cerebral Cavernous Malformation Genes Results in Accumulation of von Willebrand Factor and Redistribution of Weibel-Palade Bodies in Endothelial Cells

Intracranial venous malformation masquerading as a meningioma in PI3KCA‐related overgrowth spectrum disorder

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