Analyzing the Genetic Spectrum of Vascular Anomalies with Overgrowth via Cancer Genomics
Analyzing the Genetic Spectrum of Vascular Anomalies with Overgrowth via Cancer Genomics
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DOI：
10.1016/j.jid.2017.10.033
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发表时间：
2018-04-01
影响因子：
6.5
通讯作者：
Drolet, Beth A.
中科院分区：
文献类型：
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作者：
Siegel, Dawn H.;Cottrell, Catherine E.;Drolet, Beth A.
血管异常与过度生长、骨骼异常、脑、软脑膜和眼的异常密切相关。我们组建了一个由16家机构组成的网络，以确定与一系列血管异常过度生长相关的遗传变异范围，从轻度到重度。由于血管过度生长综合征中癌症相关变异体和先前描述的体细胞变异体之间的重叠，我们通过高深度下一代测序采用肿瘤遗传学分析，使用面板来分析来自具有过度生长的血管异常的不同受试者队列的受影响组织。75%（43/57）的患者在10个基因中存在致病性或可能致病的变异。我们确定了两个基因（mTOR，PIK 3R 1）和几个变异先前描述的癌症，但据我们所知，尚未在血管畸形中描述。所有被确定在低变异等位基因频率与体细胞镶嵌病因学一致。通过利用体细胞变异检测技术，通常适用于癌症的队列包括广泛的表型严重程度，我们证明，大多数血管异常与过度生长港口合子后功能获得性突变的癌基因。此外，继续询问良性发育障碍中的癌基因可以提供对调节细胞生长的基本机制的见解。
Vascular anomalies are variably associated with overgrowth, skeletal anomalies, and abnormalities of the brain, leptomeninges, and eye. We assembled a 16-institution network to determine the range of genetic variants associated with a spectrum of vascular anomalies with overgrowth, ranging from mild to severe. Because of the overlap between cancer-associated variants and previously described somatic variants in vascular overgrowth syndromes, we employed tumor genetic profiling via high-depth next-generation sequencing using a panel to assay affected tissue from a diverse cohort of subjects with vascular anomalies with overgrowth. Seventy-five percent (43/57) harbored pathogenic or likely pathogenic variants in 10 genes. We identified two genes (mTOR, PIK3R1) and several variants previously described in the setting of cancer but that, to our knowledge, have not been described in vascular malformations. All were identified at low variant allele frequency consistent with somatic mosaic etiology. By leveraging somatic variant detection technology typically applied to cancer in a cohort inclusive of broad phenotypic severity, we demonstrated that most vascular anomalies with overgrowth harbor postzygotic gain-of-function mutations in oncogenes. Furthermore, continued interrogation of oncogenes in benign developmental disorders could provide insight into fundamental mechanisms regulating cell growth.