Alterations of the p53, Rb and MDM2 genes in osteosarcoma
Alterations of the p53, Rb and MDM2 genes in osteosarcoma
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DOI：
10.1007/bf01213553
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发表时间：
1996-09-01
影响因子：
3.6
通讯作者：
Koeffler, HP
中科院分区：
文献类型：
--
作者：
Miller, CW;Aslo, A;Koeffler, HP
影响肿瘤抑制基因的分子缺陷是肉瘤发生的重要步骤。例如，Rb或p53基因缺陷的遗传使携带者易患骨肉瘤和其他恶性肿瘤。在这项研究中，我们评估了p53，Rb和MDM 2的改变发生在相同的骨肉瘤样本，沿着与其他各种肉瘤的代表性样本。42例骨肉瘤中有13例p53基因点突变，8例平滑肌瘤中有1例p53基因点突变，37例骨肉瘤中有5例p53基因重排。37例骨肉瘤、7例软组织肉瘤和4例Ewing肉瘤中分别有7例、1例Rb基因重排或缺失，其中5例Rb基因重排或缺失的骨肉瘤同时存在p53基因突变。MDM2癌基因的扩增和过表达可能导致MDM2-p53结合增加，从而导致p53功能失活。在37个样本中的7个中检测到MDM2拷贝数增加2至3倍，其中5个是骨肉瘤。MDM2基因的扩增独立于p53突变发生;一个MDM2扩增3倍的样品也有p53突变。总之，在42例骨肉瘤中，26例（62%）发现了34种p53、Rb和MDM2基因的改变。
Molecular defects affecting tumor-suppressor genes are an important step in the genesis of sarcomas. For example, inheritance of a defective Rb or p53 gene predisposes the carrier to develop osteosarcoma, among other malignancies. In this study, we have assessed the occurrence of p53, Rb and MDM2 alterations in the same samples of osteosarcomas, along with representative samples of various other sarcomas. Point mutations of the p53 gene were found in 13 of 42 osteosarcomas and 1 of 8 leiomyosarcomas, and gross rearrangement of the p53 gene was demonstrated in 5 of 37 osteosarcomas. The retinoblastoma susceptibility gene (Rb) was either rearranged or deleted in 7 of 37 osteosarcomas, 1 of 7 soft-tissue sarcomas and 1 of 4 Ewing sarcomas, Remarkably, 5 of the osteosarcomas having Rb alterations also had p53 mutations. Amplification and overexpression of the MDM2 oncogene may lead to increased MDM2-p53 binding resulting in inactivation of p53 function. A two- to threefold increase in the copy number of MDM2 was detected in 7 of 37 samples, 5 of which were osteosarcomas. Amplifications of the MDM2 gene occurred independently of p53 mutation; one sample having threefold amplification of MDM2 also had a p53 mutation. In summary, 34 alterations of the p53, Rb and MDM2 genes were found in 26 of 42 (62%) osteosarcomas.