Clinical, genomic, and histopathologic diversity in cerebral cavernous malformations
Abstract Cerebral cavernous malformations (CCMs) are hemorrhagic vascular disorders with varied clinical and radiological presentations, occurring sporadically due to MAP3K3 or PIK3CA mutations or through inherited germline mutations of CCM genes. This study aimed to clarify the clinical, genetic, a...
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2025-02-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-025-01940-1 |
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| author | Jian Ren Daochao Wang Leiming Wang Chendan Jiang An Tian Ziwei Cui Yeqing Ren Lisong Bian Gao Zeng Guolu Meng Yongzhi Shan Jiantao Liang Xinru Xiao Jie Tang Yukui Wei Chuan He Liyong Sun Yongjie Ma Jiaxing Yu Guilin Li Ming Ye Peng Hu Jingwei Li Ye Li Lijian Niu Qianwen Li Feng Ling Jan-Karl Burkhardt Hongqi Zhang Tao Hong |
| author_facet | Jian Ren Daochao Wang Leiming Wang Chendan Jiang An Tian Ziwei Cui Yeqing Ren Lisong Bian Gao Zeng Guolu Meng Yongzhi Shan Jiantao Liang Xinru Xiao Jie Tang Yukui Wei Chuan He Liyong Sun Yongjie Ma Jiaxing Yu Guilin Li Ming Ye Peng Hu Jingwei Li Ye Li Lijian Niu Qianwen Li Feng Ling Jan-Karl Burkhardt Hongqi Zhang Tao Hong |
| author_sort | Jian Ren |
| collection | DOAJ |
| description | Abstract Cerebral cavernous malformations (CCMs) are hemorrhagic vascular disorders with varied clinical and radiological presentations, occurring sporadically due to MAP3K3 or PIK3CA mutations or through inherited germline mutations of CCM genes. This study aimed to clarify the clinical, genetic, and pathological features of CCMs using a multicenter cohort across three Chinese centers. We analyzed 290 surgical specimens from symptomatic CCM patients, utilizing whole-exome sequencing, droplet digital PCR, and targeted panel sequencing, alongside immunohistology to examine genotypic and phenotypic differences. Among 290 cases, 201 had somatic MAP3K3, PIK3CA, or germline CCM mutations, each associated with distinct clinical parameters: hemorrhage risk (P < 0.001), lesion size (P = 0.019), non-hemorrhagic epilepsy (P < 0.001), Zabramski classifications (P < 0.001), developmental venous anomaly presence (P < 0.001), and MRI-detected edema (P < 0.001). PIK3CA mutations showed a higher hemorrhage risk than MAP3K3 and combined MAP3K3 & PIK3CA mutations (P < 0.001). Within PIK3CA mutations, the p.H1047R variant correlated with higher bleeding risk than p.E545K (P = 0.007). For non-hemorrhagic epilepsy, patients with single MAP3K3 mutations or combined MAP3K3 & PIK3CA mutations were at greater risk than those with PIK3CA mutations alone. Histopathologically, lesions with PIK3CA mutations displayed cyst walls, pS6-positive dilated capillaries, and fresh blood cells, while MAP3K3 and double mutation lesions exhibited classic CCM pathology with SMA-positive and KLF4-positive vessels, collagen, and calcification. PIK3CA lesions had fewer KLF4-positive cells than double mutations lesions (P < 0.001), and EndMT (SMA-positive) cells compared to double mutation lesions (P < 0.05) and MAP3K3 mutations (P < 0.001), with more pS6 compared to MAP3K3 mutations (P < 0.05). This study underscores the diverse clinical, genomic, and histopathological characteristics in CCMs, suggesting potential predictive markers based on mutation subtypes and MRI features. |
| format | Article |
| id | doaj-art-2f5099d3d07b4755be1c80052a1c69cf |
| institution | Kabale University |
| issn | 2051-5960 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
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| series | Acta Neuropathologica Communications |
| spelling | doaj-art-2f5099d3d07b4755be1c80052a1c69cf2025-02-09T12:59:18ZengBMCActa Neuropathologica Communications2051-59602025-02-0113111210.1186/s40478-025-01940-1Clinical, genomic, and histopathologic diversity in cerebral cavernous malformationsJian Ren0Daochao Wang1Leiming Wang2Chendan Jiang3An Tian4Ziwei Cui5Yeqing Ren6Lisong Bian7Gao Zeng8Guolu Meng9Yongzhi Shan10Jiantao Liang11Xinru Xiao12Jie Tang13Yukui Wei14Chuan He15Liyong Sun16Yongjie Ma17Jiaxing Yu18Guilin Li19Ming Ye20Peng Hu21Jingwei Li22Ye Li23Lijian Niu24Qianwen Li25Feng Ling26Jan-Karl Burkhardt27Hongqi Zhang28Tao Hong29Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Pathology, Xuanwu Hospital, Capital Medical UniversityDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Beijing Haidian HospitalDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Beijing Fengtai YouAnMen HospitalDepartment of Radiology, Xuanwu Hospital, Capital Medical UniversityDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Perelman School of Medicine, Hospital of the University of Pennsylvania, University of PennsylvaniaDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersDepartment of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National Center for Neurological DisordersAbstract Cerebral cavernous malformations (CCMs) are hemorrhagic vascular disorders with varied clinical and radiological presentations, occurring sporadically due to MAP3K3 or PIK3CA mutations or through inherited germline mutations of CCM genes. This study aimed to clarify the clinical, genetic, and pathological features of CCMs using a multicenter cohort across three Chinese centers. We analyzed 290 surgical specimens from symptomatic CCM patients, utilizing whole-exome sequencing, droplet digital PCR, and targeted panel sequencing, alongside immunohistology to examine genotypic and phenotypic differences. Among 290 cases, 201 had somatic MAP3K3, PIK3CA, or germline CCM mutations, each associated with distinct clinical parameters: hemorrhage risk (P < 0.001), lesion size (P = 0.019), non-hemorrhagic epilepsy (P < 0.001), Zabramski classifications (P < 0.001), developmental venous anomaly presence (P < 0.001), and MRI-detected edema (P < 0.001). PIK3CA mutations showed a higher hemorrhage risk than MAP3K3 and combined MAP3K3 & PIK3CA mutations (P < 0.001). Within PIK3CA mutations, the p.H1047R variant correlated with higher bleeding risk than p.E545K (P = 0.007). For non-hemorrhagic epilepsy, patients with single MAP3K3 mutations or combined MAP3K3 & PIK3CA mutations were at greater risk than those with PIK3CA mutations alone. Histopathologically, lesions with PIK3CA mutations displayed cyst walls, pS6-positive dilated capillaries, and fresh blood cells, while MAP3K3 and double mutation lesions exhibited classic CCM pathology with SMA-positive and KLF4-positive vessels, collagen, and calcification. PIK3CA lesions had fewer KLF4-positive cells than double mutations lesions (P < 0.001), and EndMT (SMA-positive) cells compared to double mutation lesions (P < 0.05) and MAP3K3 mutations (P < 0.001), with more pS6 compared to MAP3K3 mutations (P < 0.05). This study underscores the diverse clinical, genomic, and histopathological characteristics in CCMs, suggesting potential predictive markers based on mutation subtypes and MRI features.https://doi.org/10.1186/s40478-025-01940-1MAP3K3PIK3CAVascular malformationsHemorrhageEpilepsy |
| spellingShingle | Jian Ren Daochao Wang Leiming Wang Chendan Jiang An Tian Ziwei Cui Yeqing Ren Lisong Bian Gao Zeng Guolu Meng Yongzhi Shan Jiantao Liang Xinru Xiao Jie Tang Yukui Wei Chuan He Liyong Sun Yongjie Ma Jiaxing Yu Guilin Li Ming Ye Peng Hu Jingwei Li Ye Li Lijian Niu Qianwen Li Feng Ling Jan-Karl Burkhardt Hongqi Zhang Tao Hong Clinical, genomic, and histopathologic diversity in cerebral cavernous malformations Acta Neuropathologica Communications MAP3K3 PIK3CA Vascular malformations Hemorrhage Epilepsy |
| title | Clinical, genomic, and histopathologic diversity in cerebral cavernous malformations |
| title_full | Clinical, genomic, and histopathologic diversity in cerebral cavernous malformations |
| title_fullStr | Clinical, genomic, and histopathologic diversity in cerebral cavernous malformations |
| title_full_unstemmed | Clinical, genomic, and histopathologic diversity in cerebral cavernous malformations |
| title_short | Clinical, genomic, and histopathologic diversity in cerebral cavernous malformations |
| title_sort | clinical genomic and histopathologic diversity in cerebral cavernous malformations |
| topic | MAP3K3 PIK3CA Vascular malformations Hemorrhage Epilepsy |
| url | https://doi.org/10.1186/s40478-025-01940-1 |
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