Comprehensive NF1 screening on cultured Schwann cells from neurofibromas
Comprehensive NF1 screening on cultured Schwann cells from neurofibromas
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DOI：
10.1002/humu.20389
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发表时间：
2006-10-01
期刊：
影响因子：
3.9
通讯作者：
Messiaen, Ludwine
中科院分区：
文献类型：
--
作者：
Maertens, Ophelia;Brems, Hilde;Messiaen, Ludwine
1型神经纤维瘤病(NF1)以良性周围神经鞘膜瘤或神经纤维瘤的发生为主要特征。到目前为止，由于NF1基因的大小和肿瘤中相当大比例的NF1杂合子细胞，对体细胞突变谱的彻底调查受到了阻碍。我们开发了一种改进的体细胞突变检测策略，对神经纤维瘤来源的雪旺细胞进行培养，并对9名NF1患者的38个肿瘤进行了研究。检测到29个NF1体细胞病变，这是迄今为止所描述的最高的NF1体细胞突变检测率(76%)。此外，我们的数据有力地表明，后天获得的第二次打击是雪旺细胞培养中NF1表达减少的基础。总之，这些数据清楚地表明，在NF1肿瘤发生中，雪旺细胞亚群中的两个失活NF1突变是神经纤维瘤形成所必需的。体细胞突变谱显示基因内NF1突变(26/29)最为常见，尤其是移码突变(12/29，41%)。我们推测，这种突变特征可能反映了DNA修复效率的轻微降低，这是肿瘤发生前NF1体细胞失活的触发因素。对目前和以前发表的NF1突变数据的联合分析显示，NF1微缺失患者和非微缺失患者的体细胞突变谱在杂合性事件丢失的发生率方面存在显著差异(0/15比41/81)。因此，在NF1微缺失患者和普通NF1人群之间可能存在体细胞失活机制的差异。
Neurofibromatosis type 1 (NF1) is mainly characterized by the occurrence of benign peripheral nerve sheath tumors or neurofibromas. Thorough investigation of the somatic mutation spectrum has thus far been hampered by the large size of the NF1 gene and the considerable proportion of NF1 heterozygous cells within the tumors. We developed an improved somatic mutation detection strategy on cultured Schwann cells derived from neurofibromas and investigated 38 tumors from nine NF1 patients. Twenty-nine somatic NF1 lesions were detected which represents the highest NF1 somatic mutation detection rate described so far (76%). Furthermore, our data strongly suggest that the acquired second hit underlies reduced NF1 expression in Schwann cell cultures. Together, these data clearly illustrate that two inactivating NF1 mutations, in a subpopulation of the Schwann cells, are required for neurofibroma formation in NF1 tumorigenesis. The observed somatic mutation spectrum shows that intragenic NF1 mutations (26/29) are most prevalent, particularly frameshift mutations (12/29, 41%). We hypothesize that this mutation signature might reflect slightly reduced DNA repair efficiency as a trigger for NF1 somatic inactivation preceding tumorigenesis. joint analysis of the current and previously published NF1 mutation data revealed a significant difference in the somatic mutation spectrum in patients with a NF1 microdeletion vs. non-microdeletion patients with respect to the prevalence of loss of heterozygosity events (0/15 vs. 41/81). Differences in somatic inactivation mechanism might therefore exist between NF1 microdeletion patients and the general NF1 population.