Martin Planet, Yohan Ducos, Mélanie Eyries, Pauline Marijon, Franck Bielle, Lucas Rincon de la Rosa, Agusti Alentorn, Bertrand Mathon, Florence Coulet, Michel Kalamarides, Matthieu Peyre
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引用次数: 0
Abstract
Objective: 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.
Methods: 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.
Results: 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).
Conclusions: 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.
目的:自2021年以来,随着PIK3CA和MAP3K3基因体细胞突变的关键发现,对散发性脑海绵状血管病(CCMs)突变格局的理解发生了一场革命。这些基因改变为CCMs的病理生理学提供了新的见解,并为个性化治疗开辟了潜在的场所。然而,建立强有力的临床放射学和分子相关性对于指导靶向治疗方法和优化患者预后至关重要。方法:本研究纳入了89例诊断为散发性CCMs的患者。每位患者的突变状态使用针对已知突变的下一代测序(NGS)确定,包括PIK3CA, MAP3K3和CCM基因。通过PIK3CA和MAP3K3突变的液滴数字聚合酶链反应证实了NGS的发现。系统记录临床和放射学资料,包括Zabramski分类资料。进行统计分析以确定显著的临床放射学和分子相关性。结果:在队列中,43例(48%)患者发现PIK3CA体细胞突变,29例(33%)患者发现MAP3K3体细胞突变。临床上,pik3ca突变病变在颅内高压中较少被发现(9.3% vs 19.6%;校正OR 0.09, p = 0.006),而在map3k3突变病变中,癫痫发作作为发病方式的频率明显更高(85.7% vs 51.7%, p = 0.002)。放射学上,pik3ca突变组中线病变明显更频繁(19.0% vs 2.2%, p = 0.01)。重要的是,在单变量分析中,脑干病变的存在是PIK3CA体细胞突变的重要独立预测因子(14.3% vs 2.2%;未经调整的OR为7.33,p = 0.03)。结论:本研究提出了将基因突变与散发性CCMs的临床放射学特征联系起来的新发现。PIK3CA体细胞突变与脑干位置的显著关联突出了针对该突变的个性化治疗策略的潜在途径,考虑到脑干病变相关的发病率显著增加和手术挑战。这些发现强调了将遗传数据整合到临床实践中以改善患者预后和开发CCMs新疗法的重要性。
期刊介绍:
The Journal of Neurosurgery, Journal of Neurosurgery: Spine, Journal of Neurosurgery: Pediatrics, and Neurosurgical Focus are devoted to the publication of original works relating primarily to neurosurgery, including studies in clinical neurophysiology, organic neurology, ophthalmology, radiology, pathology, and molecular biology. The Editors and Editorial Boards encourage submission of clinical and laboratory studies. Other manuscripts accepted for review include technical notes on instruments or equipment that are innovative or useful to clinicians and researchers in the field of neuroscience; papers describing unusual cases; manuscripts on historical persons or events related to neurosurgery; and in Neurosurgical Focus, occasional reviews. Letters to the Editor commenting on articles recently published in the Journal of Neurosurgery, Journal of Neurosurgery: Spine, and Journal of Neurosurgery: Pediatrics are welcome.