Lesions from patients with sporadic cerebral cavernous malformations harbor somatic mutations in the CCM genes: evidence for a common biochemical pathway for CCM pathogenesis
Lesions from patients with sporadic cerebral cavernous malformations harbor somatic mutations in the CCM genes: evidence for a common biochemical pathway for CCM pathogenesis
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DOI：
10.1093/hmg/ddu153
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发表时间：
2014-08-15
影响因子：
3.5
通讯作者：
Marchuk, Douglas A.
中科院分区：
文献类型：
--
作者：
McDonald, David A.;Shi, Changbin;Marchuk, Douglas A.
脑海绵状血管瘤（CCM）是影响中枢神经系统的血管病变。 CCM 可以偶发发生，也可以以常染色体显性遗传方式发生。 KRIT1、CCM2 和 PDCD10 三个基因中任何一个的宪法（种系）突变都可能导致遗传形式。对遗传病例 CCM 病变的分析揭示了双等位体细胞突变，表明 CCM 遵循努森两次突变机制。然而，目前尚不清楚散发的 CCM 病例是否也遵循这种遗传机制。我们从散发性 CCM 患者的 11 个手术切除的病灶中提取了 DNA，并使用下一代测序方法对每个样本中的 3 个 CCM 基因进行了测序。四个散发性 CCM 病变样本 (36%) 被发现含有新的体细胞突变。其中三个病变包含单个体细胞突变，一个病变包含两个双等位体细胞突变。在此，我们还描述了一名患者的体细胞镶嵌证据，该患者的大脑一侧半球有超过 130 个 CCM 病变。最后，在病变再生样本中，我们发现再生的 CCM 病变包含与原始病变相同的体细胞突变。总之，这些数据支持了这样的观点：所有形式的 CCM 都具有已知 CCM 基因中的两次突变机制的遗传基础。最近的研究发现遗传性 CCM 发病机制中存在异常的 Rho 激酶激活，我们提供的证据表明该通路在散发性 CCM 患者中被激活。这些结果表明，所有 CCM 患者，包括那些更常见的散发型患者，都可能适合相同的治疗。
Cerebral cavernous malformations (CCMs) are vascular lesions affecting the central nervous system. CCM occurs either sporadically or in an inherited, autosomal dominant manner. Constitutional (germline) mutations in any of three genes, KRIT1, CCM2 and PDCD10, can cause the inherited form. Analysis of CCM lesions from inherited cases revealed biallelic somatic mutations, indicating that CCM follows a Knudsonian two-hit mutation mechanism. It is still unknown, however, if the sporadic cases of CCM also follow this genetic mechanism. We extracted DNA from 11 surgically excised lesions from sporadic CCM patients, and sequenced the three CCM genes in each specimen using a next-generation sequencing approach. Four sporadic CCM lesion samples (36%) were found to contain novel somatic mutations. Three of the lesions contained a single somatic mutation, and one lesion contained two biallelic somatic mutations. Herein, we also describe evidence of somatic mosaicism in a patient presenting with over 130 CCM lesions localized to one hemisphere of the brain. Finally, in a lesion regrowth sample, we found that the regrown CCM lesion contained the same somatic mutation as the original lesion. Together, these data bolster the idea that all forms of CCM have a genetic underpinning of the two-hit mutation mechanism in the known CCM genes. Recent studies have found aberrant Rho kinase activation in inherited CCM pathogenesis, and we present evidence that this pathway is activated in sporadic CCM patients. These results suggest that all CCM patients, including those with the more common sporadic form, are potentially amenable to the same therapy.