Molecular analysis of p53, MDM2, and H-ras genes in osteosarcoma and malignant fibrous histiocytoma of bone in patients older than 40 years
Molecular analysis of p53, MDM2, and H-ras genes in osteosarcoma and malignant fibrous histiocytoma of bone in patients older than 40 years
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DOI：
10.1097/01.mp.0000024264.48690.ea
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发表时间：
2002-08-01
期刊：
影响因子：
7.5
通讯作者：
Tsuneyoshi, M
中科院分区：
文献类型：
--
作者：
Kawaguchi, K;Oda, Y;Tsuneyoshi, M
一些研究者报道骨肉瘤的组织学特征。(OS)在老年患者中发生的OS与年轻患者不同;然而，尚未记录老年患者中OS的分子生物学研究。在这项研究中，23例OS（15成骨细胞型和8 MFH样型）和18例MFH的骨患者40岁或以上的p53基因突变，MDM 2基因扩增，和H-ras基因突变进行了分析，使用福尔马林固定石蜡包埋材料。我们还检测了p53、MDM 2和p21 WAF 1蛋白的表达，并使用单克隆抗体M1 B-1评估了增殖活性。23例OS中5例（22%）检测到p53免疫反应性，而23例OS中5例（22%;成骨细胞型[4/15; 27%]和MFH样型[18; 18%]）和18例骨MFH中4例（22%）也检测到p53基因突变。OS中p53免疫反应性和p53突变状态之间存在统计学显著相关性（P = 0.0482）。所有这些成骨细胞OS和骨MFH的病例，有p53突变，除了1例骨MFH的沉默突变，表现出积极的生物学行为（12个月内死于疾病），与MFH样OS病例（22个月时无疾病存活）。3例OS（13%）和3例骨MFH（17%）显示MDM 2免疫反应性。在基因改变方面，3例OS（13%）和3例骨MFH（17%）显示MDM 2扩增。MDM 2扩增与OS中MDM 2蛋白表达显著相关（P = 0.0344）。p21 WAF 1在3例OS（13%）和6例MFH（33%）中表达。在任何MFH样OS病例中均未观察到MDM 2改变和p21 WAF 1表达。MIB-1-LI与OS中的p53免疫反应性和MDM 2免疫反应性呈统计学显著相关（分别为P =.0307和P =.0358）。在骨OS和MFH病例中均未发现H-ras基因第12和13位密码子突变。总之，尽管研究期间的治疗差异使得难以比较生存分析，但在本研究中，老年患者成骨细胞OS和骨MFH中的p53突变似乎与肿瘤进展密切相关，而MFH样OS的情况并非如此。此外，MDM 2改变和p21 WAF 1表达仅在成骨细胞OS和骨MFH中得到证实，尽管本分析中的患者数量较少，但与老年患者的成骨细胞OS和骨MFH相比，MFH样OS可能具有一些特征性的生物学方面。
Some investigators have reported that the histological features of osteosarcoma. (OS) arising in elderly patients are different from those in younger patients; however, a molecular biologic study of OS in elderly patients has not been documented. In this study, 23 cases of OS (15 osteoblastic and 8 MFH-like types) and 18 cases of MFH of bone in patients 40 years of age or older were analyzed for mutation of the p53 gene, amplification of the MDM2 gene, and mutation of the H-ras gene, using formalin-fixed paraffin-embedded materials. We also examined the expression of p53, MDM2, and p21WAF1 protein immunohistochemically and assessed the proliferative activities using the monoclonal antibody MlB-1. p53 immunoreactivity was recognized in 5 of 23 OS cases (22%), whereas p53 gene mutations were also detected in 5 of 23 OS cases (22%; osteoblastic [4/15; 27%] and MFH-like [1/8; 18%] types) and in 4 of 18 cases of MFH of bone (22%). There was a statistically significant correlation between p53 immunoreactivity and p53 mutation status in OS (P =.0482). All those cases of osteoblastic OS and MFH of bone that had p53 mutations, with the exception of one case of MFH of bone that had a silent mutation, showed aggressive biologic behavior (dead of disease within 12 mo), in contrast to the MFH-like OS cases (alive without disease at 22 mo). Three cases of OS (13%) and three cases of MFH of bone (17%) showed immunoreactivity for MDM2. As for gene alteration, three cases of OS (13%) and 3 cases of MFH of bone (17%) demonstrated MDM2 amplification. MDM2 amplification showed a significant correlation with the expression of MDM2 protein in OS (P =.0344). p21WAF1 expression was detected in three cases of OS (13%) and in six cases of MFH of bone (33%). MDM2 alteration and p21WAF1 expression were not observed in any of the cases of MFH-like OS. MIB-1-LI showed a statistically significant correlation with p53 immunoreactivity and MDM2 immunoreactivity in OS (P =.0307 and P =.0358, respectively). H-ras mutation at Codons, 12 and 13 was not recognized in any of the cases of OS or MFH of bone. In conclusion, although treatment differences during the time of study make it difficult to compare survival analysis, in the current study, p53 mutation in osteoblastic OS and MFH of bone in elderly patients seemed to be closely associated with the progression of the tumor, which was not the case in MFH-like OS. Furthermore, MDM2 alteration and p21WAF1 expression were demonstrated only in osteoblastic OS and MFH of bone, whereas they were not recognized in MFH-like OS. Although the number of patients in this analysis was small, it would appear that MFH-like OS may have some characteristic biologic aspects when compared with osteoblastic OS and MFH of bone in elderly patients.