HIGH-FREQUENCY OF INACTIVATING MUTATIONS IN THE NEUROFIBROMATOSIS TYPE-2 GENE (NF2) IN PRIMARY MALIGNANT MESOTHELIOMAS
HIGH-FREQUENCY OF INACTIVATING MUTATIONS IN THE NEUROFIBROMATOSIS TYPE-2 GENE (NF2) IN PRIMARY MALIGNANT MESOTHELIOMAS
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DOI：
10.1073/pnas.92.24.10854
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发表时间：
1995-11-21
影响因子：
11.1
通讯作者：
TESTA, JR
中科院分区：
文献类型：
--
作者：
BIANCHI, AB;MITSUNAGA, SI;TESTA, JR
恶性间皮瘤（malignant mesotheliomas，简称MM）是一种侵袭性肿瘤，最常发生在接触石棉的患者的胸膜中。与许多其他癌症相比，MM中描述的分子改变相对较少。MM中最常见的细胞遗传学异常是22号染色体的丢失，2型神经纤维瘤病基因（NF 2）是染色体22 q上的肿瘤抑制基因，其在神经外胚层起源的家族性和自发性肿瘤的发展中起重要作用，虽然MM具有不同的组织发生学来源，但22号染色体的频繁异常保证了对这些肿瘤中NF 2基因的研究。分析了来自15个MM细胞系的cDNA和来自7个匹配的原发性肿瘤的基因组DNA在NF 2编码区内的突变。在8个细胞系（53%）中检测到预测NF 2编码蛋白（merlin）的间质框内缺失或截短的NF 2突变，其中6个在原发性肿瘤DNA中得到证实。在显示NF 2基因转录物改变的两个样品中，未检测到基因组DNA突变，表明异常剪接可能构成merlin失活的额外机制，这些发现暗示NF 2在原发性MM的肿瘤发生中，并提供证据表明该基因可参与NF 2紊乱特征的神经系统肿瘤以外的肿瘤的发展。此外，与NF 2相关肿瘤不同，MM源自中胚层;这种起源的恶性肿瘤以前与NF 2基因的频繁改变无关。
Malignant mesotheliomas (MMs) are aggressive tumors that develop most frequently in the pleura of patients exposed to asbestos, In contrast to many other cancers, relatively few molecular alterations have been described in MMs, The most frequent numerical cytogenetic abnormality in MMs is loss of chromosome 22, The neurofibromatosis type 2 gene (NF2) is a tumor suppressor gene assigned to chromosome 22q which plays an important role in the development of familial and spontaneous tumors of neuroectodermal origin, Although MMs have a different histogenic derivation, the frequent abnormalities of chromosome 22 warranted an investigation of the NF2 gene in these tumors, Both cDNAs from 15 MM cell lines and genomic DNAs from 7 matched primary tumors were analyzed for mutations within the NF2 coding region. NF2 mutations predicting either interstitial in-frame deletions or truncation of the NF2-encoded protein (merlin) were detected in eight cell lines (53%), six of which were confirmed in primary tumor DNAs, In two samples that showed NF2 gene transcript alterations, no genomic DNA mutations were detected, suggesting that aberrant splicing may constitute an additional mechanism for merlin inactivation, These findings implicate NF2 in the oncogenesis of primary MMs and provide evidence that this gene can be involved in the development of tumors other than nervous system neoplasms characteristic of the NF2 disorder, In addition, unlike NF2-related tumors, MM derives from the mesoderm; malignancies of this origin have not previously been associated with frequent alterations of the NF2 gene.