散发脊髓神经鞘瘤病22号染色体变异的初步分析

Gene mutation at chromosome 22 in sporadic patients with spinal schwannomatosis:A preliminary analysis

目的初步探讨散发脊髓神经鞘瘤病与22号染色体突变的相关性。方法前瞻性纳入北京大学第三医院神经外科2015年5月至12月收治的9例脊髓多发肿瘤患者,其中4例行颈椎管内肿瘤切除术,4例行腰椎管内肿瘤切除术,另1例行胸、腰椎管内肿瘤切除术治疗。术中留取患者的血液标本和肿瘤组织标本。术后进行外显子测序,以判断单核苷酸多样性(SNP)、单核苷酸变异性(SNV)及外显子基因拷贝数变异(CNV)。结果9例患者的手术均成功。病理学检查结果,3例为神经纤维瘤病Ⅰ型,1例为神经节细胞瘤,1例为室管膜瘤,4例为脊髓神经鞘瘤病(其中1例伴双侧听神经鞘瘤)。外显子测序结果为,9例患者中,4例脊髓神经鞘瘤患者均存在22号染色体的基因突变,其中2例发生在生殖细胞水平,1例为神经纤维瘤病Ⅱ型(NF2)位点高频剪切突变(T→C),1例为亮氨酸拉链样转录调节因子1(LZTR1)位点高频移码突变(G→GT);另2例发生在体细胞水平,其中1例为NF2高频移码突变(CGA→C),1例为NF2高频Stop-gain突变。发生22号染色体突变的4例患者中,2例同时合并19号染色体原纤蛋白3(FBN3)位点中频错义突变(G→A),其中1例发生在体细胞水平,1例发生在生殖细胞水平。结论初步提示脊髓神经鞘瘤病中发生高频突变的基因大多在22号染色体上。

Objective To analyze the correlation on the prominent germline or somatic mutations at chromosome 22 of the sporadic patients with spinal schwannomatosis.Methods From May to November 2015,9 serial patients with multiple spinal cord tumors underwent open surgery at Neurosurgical Department,the Third Hospital of Peking University.All spinal cord tumors in the 9 patients were removed by operation.The multiple spinal cord tumors were located at lumbar segments in 4 patients,at cervical segments in 4,and at thoracolumbar segments in 1.The samples of tumor and blood were preserved during operation.In order to determine the SNP(single nucleotide polymorphism),SNV(single nucleotide variants)and CNV(copy number variations)of 9 patients,whole-exome targeted enrichment and sequencing were performed on tumor and blood DNA after operation.Results The open surgery was successful performed in 9 patients.Among 9 patients,histological staining showed neurofibromatosis type I(NF1)in 3 cases,ganglioneuroma in 1,ependymoma in 1,and schwannomatosis in 4(1 case with comorbidity of bilateral acoustic tumors).Among 9 sporadic cases,gene mutation was detected in a large region of chromosome 22 only in 4 cases with spinal schwannomatosis.Among 4 cases,the germline mutation was identified in 2 cases,and somatic mutation in 2 cases.Splice-donor neurofibromatosis type 2(NF2)germline high frequency mutation(T→C)was identified in the No.1 patient.Frame-shift leucine-zipper-like transcriptional regulator 1(LZTR1)germline high frequency mutation(G→GT)was identified in the No.2 patient.Frameshift NF2 somatic mutation(CGA→C)was identified in the No.3 patient.Stop-gained NF2 somatic mutation was identified in the No.4 patient.Among 4 cases,chromosome fibrillin 3(FBN3)intermediate frequency missense mutation was simultaneously found in chromosome 19 in 2 cases,out of which 1 was somatic mutation and the other was germ line mutation.Conclusion The preliminary results have suggested that most of the genes with high frequency mutations in spinal schwannomatosis are on chromosome 22.