Mechanisms of Loss of Heterozygosity in Neurofibromatosis Type 1-Associated Plexiform Neurofibromas
Mechanisms of Loss of Heterozygosity in Neurofibromatosis Type 1-Associated Plexiform Neurofibromas
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DOI：
10.1038/jid.2008.274
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发表时间：
2009-03-01
影响因子：
6.5
通讯作者：
Kehrer-Sawatzki, Hildegard
中科院分区：
文献类型：
--
作者：
Steinmann, Katharina;Kluwe, Lan;Kehrer-Sawatzki, Hildegard
丛状神经纤维瘤是1型神经纤维瘤病（NF 1）患者的严重负担，NF 1是一种常见的常染色体显性遗传疾病，其特征为色素改变和肿瘤性皮肤病变（神经纤维瘤）。尽管这些良性肿瘤在NF 1患者中很突出，但丛状神经纤维瘤中肿瘤相关杂合性缺失（洛）的机制尚未得到广泛研究。我们对31例NF 1患者的43例丛状神经纤维瘤进行了洛缺失分析，这是迄今为止同类研究中最大的一次。丛状神经纤维瘤13例（30%）出现17 q标记的洛缺失。在三个肿瘤中，发现洛仅限于NF 1基因区域。然而，在所有肿瘤中均未检测到由NF 1-REP或SUZ 12基因之间的非等位基因同源重组介导的体细胞NF 1微缺失。因此，在丛状神经纤维瘤中，NF 1微缺失似乎不是常见的体细胞事件。通过多重连接依赖探针扩增确定NF 1基因拷贝数表明，尽管洛区域较小的肿瘤以17 q缺失为特征，但在6例具有更广泛洛的丛状神经纤维瘤中未检测到NF 1基因拷贝数的变化。据我们所知，有丝分裂重组以前没有被报道是导致丛状神经纤维瘤洛缺失的常见原因。
Plexiform neurofibromas constitute a serious burden for patients with neurofibromatosis type 1 (NF1), a common autosomal dominant disorder characterized by pigmentary changes and tumorous skin lesions (neurofibromas). Despite the prominence of these benign tumors in NF1 patients, the mechanisms underlying the tumor-associated loss of heterozygosity (LOH) in plexiform neurofibromas have not been extensively studied. We performed LOH analysis on 43 plexiform neurofibromas from 31 NF1 patients, the largest study of its kind to date. A total of 13 (30%) plexiform neurofibromas exhibited LOH involving 17q markers. In three tumors, LOH was found to be confined to the NF1 gene region. However, in none of the tumors was a somatic NF1 microdeletion, mediated by non-allelic homologous recombination between either NF1-REPs or SUZ12 genes, detected. Thus, NF1 microdeletions do not appear to be frequent somatic events in plexiform neurofibromas. Determination of NF1 gene copy number by multiplex ligation-dependent probe amplification indicated that although tumors with smaller regions of LOH were characterized by 17q deletions, no NF1 gene copy number changes were detected in six plexiform neurofibromas with more extensive LOH. To our knowledge, mitotic recombination has not previously been reported to be a frequent cause of LOH in plexiform neurofibromas.