The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis.
The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis.
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Schwannomatosis的分子发病机理，这是多种肿瘤抑制基因在肿瘤发生中共同参与的范例。
DOI：
10.1007/s00439-016-1753-8
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发表时间：
2017-02
期刊：
影响因子：
5.3
通讯作者：
Cooper DN
中科院分区：
文献类型：
--
作者：
Kehrer-Sawatzki H;Farschtschi S;Mautner VF;Cooper DN
神经鞘瘤病的特点是易发生多发性神经鞘瘤，脑膜瘤较少见。尽管与神经纤维瘤病2型（NF 2）的临床重叠，神经鞘瘤病不是由生殖系NF 2基因突变引起的。相反，在86%的家族性和40%的散发性神经鞘瘤病患者中发现了SMARCB 1或LZTR 1肿瘤抑制基因的种系突变。与横纹肌样瘤患者（由于SMARCB 1突变完全丧失功能）相反，神经鞘瘤病患者主要携带亚型SMARCB 1突变，导致合成具有残留功能的突变蛋白，不会引起横纹肌样瘤。尽管在神经鞘瘤病患者的肿瘤中检测到SMARCB 1或LZTR 1的双等位基因突变，但经典的肿瘤发生的两次打击模型不足以解释神经鞘瘤的生长，因为NF 2在这些肿瘤中也经常失活。因此，神经鞘瘤病的肿瘤发生必须涉及至少两种不同的肿瘤抑制基因的突变，这种突变经常由染色体22 q的大部分杂合性缺失介导，所述杂合性缺失不仅包含SMARCB 1和LZTR 1，而且还包含NF 2。因此，神经鞘瘤病是由两个或多个肿瘤抑制基因的伴随突变失活引起的肿瘤易感综合征的范例。本文综述了神经鞘瘤病的肿瘤发生和突变模式，最终将有助于解释这种罕见疾病的复杂的临床表现。本文的在线版本（doi：10.1007/s 00439 -016-1753-8）包含补充材料，可供授权用户使用。
Schwannomatosis is characterized by the predisposition to develop multiple schwannomas and, less commonly, meningiomas. Despite the clinical overlap with neurofibromatosis type 2 (NF2), schwannomatosis is not caused by germline NF2 gene mutations. Instead, germline mutations of either the SMARCB1 or LZTR1 tumour suppressor genes have been identified in 86% of familial and 40% of sporadic schwannomatosis patients. In contrast to patients with rhabdoid tumours, which are due to complete loss-of-function SMARCB1 mutations, individuals with schwannomatosis harbour predominantly hypomorphic SMARCB1 mutations which give rise to the synthesis of mutant proteins with residual function that do not cause rhabdoid tumours. Although biallelic mutations of SMARCB1 or LZTR1 have been detected in the tumours of patients with schwannomatosis, the classical two-hit model of tumorigenesis is insufficient to account for schwannoma growth, since NF2 is also frequently inactivated in these tumours. Consequently, tumorigenesis in schwannomatosis must involve the mutation of at least two different tumour suppressor genes, an occurrence frequently mediated by loss of heterozygosity of large parts of chromosome 22q harbouring not only SMARCB1 and LZTR1 but also NF2. Thus, schwannomatosis is paradigmatic for a tumour predisposition syndrome caused by the concomitant mutational inactivation of two or more tumour suppressor genes. This review provides an overview of current models of tumorigenesis and mutational patterns underlying schwannomatosis that will ultimately help to explain the complex clinical presentation of this rare disease. The online version of this article (doi:10.1007/s00439-016-1753-8) contains supplementary material, which is available to authorized users.