Cavernous malformations (CMs) affecting the central nervous system occur in approximately 0.16% to 0.4% of the general population. The majority (85%) of the CMs are in a sporadic form, but the genetic background of sporadic CMs remains enigmatic. Of the 81 patients, 73 (90.1%) patients were detected carrying somatic missense variants in 2 genes: MAP3K3 and PIK3CA by whole-exome sequencing (WES). The mutation spectrum correlated with lesion size (P = 0.001), anatomical distribution (P < 0.001), MRI appearance (P = 0.004) and haemorrhage events (P = 0.006). PIK3CA mutation was a significant predictor of overt haemorrhage events (P = 0.003, OR = 11.252, 95% CI = 2.275-55.648). Enrichment of endothelial cell (EC) population was associated with a higher fractional abundance of the somatic mutations. Overexpression of the MAP3K3 mutation perturbed angiogenesis of EC models in vitro and zebrafish embryos in vivo. Distinct transcriptional signatures between different genetic subgroups of sporadic CMs were identified by single-cell RNA-sequencing (scRNA-seq) and verified by pathological staining. Significant apoptosis in MAP3K3 mutation carriers and overexpression of GDF15 and SERPINA5 in PIK3CA mutation carriers contributed to their phenotype. We identified activating MAP3K3 and PIK3CA somatic mutations in the majority (90.1%) of sporadic CMs and PIK3CA mutations could confer a higher risk for overt haemorrhage. Our data provide insights into genomic landscapes, propose a mechanistic explanation and underscore the possibility of a molecular classification for sporadic CMs.

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OBJECTIVEOptimal surgical strategies for intramedullary spinal cord cavernous malformations (ISCCMs) are not optimized and remain problematic. In this study the authors identify rational surgical strategies for ISCCMs and predictors of outcomes after resection.METHODSA single-center study was performed with 219 consecutive surgically treated patients who presented from 2002 to 2017 and were analyzed retrospectively. The American Spinal Injury Association (ASIA) Impairment Scale was used to evaluate neurological functions. Patient characteristics, surgical approaches, and immediate and long-term postoperative outcomes were identified.RESULTSThe average ISCCM size was 10.5 mm. The spinal level affected was cervical in 24.8% of patients, thoracic in 73.4%, and lumbar in 1.8%. The locations of the lesions in the horizontal plane were 30.4% ventral, 41.6% dorsal, and 28.0% central. Of the 214 patients included in the cohort for operative evaluation, 62.6% had superficially located lesions, while 37.4% were embedded. Gross-total resection was achieved in 98.1% of patients. The immediate postoperative neurological condition worsened in 10.3% of the patients. Multivariate logistic regression identified mild preoperative function (p = 0.014, odds ratio [OR] 4.5, 95% confidence interval [CI] 1.4–14.8) and thoracolumbar-level lesions (p = 0.01, OR 15.7, 95% CI 1.9–130.2) as independent predictors of worsening. The mean follow-up duration in 187 patients was 45.9 months. Of these patients, 63.1% were stable, 33.2% improved, and 3.7% worsened. Favorable outcomes were observed in 86.1% of patients during long-term follow-up and were significantly associated with preoperative mild neurological and disability status (p = 0.000) and cervically located lesions (p = 0.009). The depths of the lesions were associated with worse long-term outcomes (p = 0.001), and performing myelotomy directly through a yellowish abnormal surface in moderate-depth lesions was an independent predictor of worsening (p = 0.023, OR 35.3, 95% CI 1.6–756.3).CONCLUSIONSResection performed with an individualized surgical approach remains the primary therapeutic option in ISCCMs. Performing surgery in patients with mild symptoms at the thoracolumbar level and embedded located lesions requires more discretion.