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Developmental venous anomalies are a genetic primer for cerebral cavernous malformations

Abstract

Cerebral cavernous malformations (CCMs) are a neurovascular anomaly that may occur sporadically or be inherited due to autosomal dominant mutations in KRIT1, CCM2 or PDCD10 (refs. 1,2,3,4). Individual lesions are caused by somatic mutations that have been identified in KRIT1, CCM2, PDCD10, MAP3K3 and PIK3CA5,6,7,8,9,10,11. However, the interactions between mutations and their relative contributions to sporadic versus familial cases are unclear. We show that mutations in KRIT1, CCM2, PDCD10 and MAP3K3 are mutually exclusive but may co-occur with mutations in PIK3CA. We also find that MAP3K3 mutations may cause sporadic but not familial CCM. Furthermore, we find identical PIK3CA mutations in CCMs and adjacent developmental venous anomalies (DVAs), a common vascular malformation frequently found in the vicinity of sporadic CCMs12,13,14. However, somatic mutations in MAP3K3 are found only in the CCM. This suggests that sporadic CCMs are derived from cells of the DVA that have acquired an additional mutation in MAP3K3.

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Fig. 1: Mutations in MAP3K3 are mutually exclusive with CCM gene mutations and occur in the same cells as PIK3CA mutations.
Fig. 2: Associated CCMs and DVAs harbor identical somatic mutations in PIK3CA.
Fig. 3: Genetic model of CCM pathogenesis.

Data availability

Data not included in this paper can be accessed through the National Center for Biotechnology Information (DNA sequencing, BioProject accession no. PRJNA802805) or Gene Expression Omnibus (RNA sequencing, accession no. GSE195732). The public datasets used in this study are available at the COSMIC (cancer.sanger.ac.uk/cosmic), dbSNP (ncbi.nlm.nih.gov/snp), 1000 Genomes Project (internationalgenome.org), gnomAD (gnomad.broadinstitute.org), miRWalk 3.0 (mirwalk.umm.uni-heidelberg.de) and DAVID databases (david.ncifcrf.gov).

Code availability

The variant calling software was implemented as part of gonomics, an ongoing effort to develop an open-source genomics platform in the Go programming language.

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Acknowledgements

We thank the patients who donated tissue for this study. We thank the Angioma Alliance, Barrow Neurological Institute and University of Chicago for patient enrollment and sample collection. Nucleus sorting was performed in the Duke Human Vaccine Institute Research Flow Cytometry Shared Resource Facility. We thank Duke University School of Medicine for the use of the Sequencing and Genomic Technologies Shared Resource for library preparation and sequencing. These studies were supported by National Institutes of Health grant nos. P01NS092521 (D.A.M., I.A.A., M.L.K.) and F31HL152738 (D.A.S.).

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D.A.S. designed and performed the genetic studies of human CCM lesions and wrote the manuscript. I.A.A. performed the surgical resection of the CCM and DVA samples used in this study. R.G., R.L., A.S., S.R., Y.L., C.C. and I.A.A. performed the plasma miRNA sequencing and analysis. A.A.R. and M.L.K. assisted with experimental design. R.G., I.A.A. and D.A.M. designed the experiments and wrote the manuscript.

Corresponding authors

Correspondence to Issam A. Awad or Douglas A. Marchuk.

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Competing interests

I.A.A. is Chairman of the scientific advisory board for the Angioma Alliance and provides expert opinions related to clinical care of CCMs. The other authors declare no competing interests.

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Nature Cardiovascular Research thanks Matteo Malinverno, Murat Gunel and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Snellings, D.A., Girard, R., Lightle, R. et al. Developmental venous anomalies are a genetic primer for cerebral cavernous malformations. Nat Cardiovasc Res 1, 246–252 (2022). https://doi.org/10.1038/s44161-022-00035-7

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