Association of PIK3CA mutations with brainstem location in sporadic cerebral cavernous malformations

Since 2021, there has been a revolution in the understanding of the mutational landscape of sporadic cerebral cavernous malformations (CCMs), with the key discovery of somatic mutations in the PIK3CA and MAP3K3 genes. These genetic alterations have provided new insights into the pathophysiology of CCMs and opened potential venues for personalized treatments. However, establishing robust clinicoradiological and molecular correlations is essential to guide targeted therapeutic approaches and optimize patient outcomes.

This study included a cohort of 89 patients diagnosed with sporadic CCMs. The mutational status of each patient was determined using next-generation sequencing (NGS) targeting known mutations including the PIK3CA, MAP3K3, and CCM genes. NGS findings were confirmed by droplet digital polymerase chain reaction for PIK3CA and MAP3K3 mutations. Clinical and radiological data, including Zabramski classification data, were systematically recorded. Statistical analysis was performed to identify significant clinicoradiological and molecular correlations.

In the cohort, PIK3CA somatic mutations were identified in 43 patients (48%), while MAP3K3 somatic mutations were found in 29 (33%). Clinically, PIK3CA-mutated lesions were less frequently revealed by intracranial hypertension (9.3% vs 19.6%; adjusted OR 0.09, p = 0.006), while for MAP3K3-mutated lesions, seizure as a mode of onset was significantly more frequent (85.7% vs 51.7%, p = 0.002). Radiologically, midline lesions were significantly more frequent in the PIK3CA-mutated group (19.0% vs 2.2%, p = 0.01). Importantly, in univariate analysis, the presence of a brainstem lesion was a significant independent predictor of PIK3CA somatic mutation (14.3% vs 2.2%; unadjusted OR 7.33, p = 0.03).

This study presents new findings linking genetic mutations with clinicoradiological features in sporadic CCMs. The significant association of PIK3CA somatic mutations with brainstem location highlights a potential avenue for personalized therapeutic strategies targeting this mutation, considering the significantly increased morbidity and surgical challenge associated with brainstem lesions. These findings reinforce the importance of integrating genetic data into clinical practice to improve patient outcomes and develop new therapies for CCMs.