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

Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations

“…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).…”

“…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 .…”

“…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.…”

“…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.…”

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

“…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).…”