骨肉瘤中ErbB受体家族的基因突变和表达变化的临床意义

The therapeutic efficacy of osteosarcoma (OSS) is not ideal currently, there is an urgent need to identify the valuable biomarkers with an aim at improving development of targeted drugs and the outcome of the disease ultimately through performing in-depth study at the molecular level. The roles of ErbB receptor family in the pathogenesis of the OSS has received little attention so far. This project is designed to characterize the gene mutation and protein expression change in each of the receptor family members in the ordinary OSS, which accounts for over 90% among all the occurring OSS, by integratedly applying the sophisticated technologies including fluorescence in situ hybridization, immunohistochemistry, quantitative PCR, DNA routine and whole genome sequencing as well as array-based comparative genome hybridization to a large number of the samples. This is followed by assessing the relevance of the changes to the profiles of the recurrence and metastasis, histological subtype, prognosis and so on of the disease. The study will be the first to reveal the intrinsic link among these parameters, and help confirm the clinical significance of ErbB family in the targeted therapy while very possibly identifying some new molecular markers, so that this will be greatly beneficial for introducing the targeted therapy concept into the OSS clinics and for optimizing the therapy plans, ultimately improving the disease prognosis. The research has not been reported so far, and is innovative and reliable. The completion of the project is of great significance to the clinics of the OSS.

骨肉瘤（OSS）的治疗效果目前还不够理想，迫切需要在分子水平深入研究，以探寻有价值的生物标志物，促进靶向药物研发，最终改善其疗效和预后。ErbB受体家族在OSS发病中的作用至今缺乏研究。本课题拟应用荧光原位杂交、免疫组织化学、定量PCR、DNA常规和全基因组测序及微阵列比较基因组杂交等方法和技术，从不同角度和层面上鉴定大量占该病发病总数90%以上的普通型OSS组织标本中该受体家族全部成员的基因突变和蛋白质表达变化，并探讨这些变化与该病复发与转移倾向、病理组织学分型和预后等参数间的相关性。此项研究的开展，将首次全面揭示这些参数间的内在联系和变化规律，将确定ErbB受体家族各成员在OSS靶向治疗中的意义和很有可能发现新的分子标志物，从而将有利于在OSS的临床治疗中引入靶向治疗的概念和治疗方案的改进，明显改善其预后。本项研究具有新颖、全面、细致和可靠的特点，对OSS的临床有举足轻重的意义。

近二三十年来骨肉瘤（OSS）的临床治疗效果处于平台期，迫切需要在分子水平进一步深入研究，探讨更有价值的生物标志物，促进靶向药物研发，最终改善其疗效和预后。ErbB受体家族在多种恶性肿瘤的发病中起着重要的作用，但其在骨肉瘤中的作用至今缺乏相关的研究。本项目通过荧光原位杂交方法对骨肉瘤组织进行基因扩增研究，发现20%-40%的骨肉瘤组织标本中出现了EGFR、HER3、HER4基因扩增，而HER2基因并未发现明显的扩增现象；在此基础上通过免疫组织化学方法对骨肉瘤组织切片进行染色，结果显示20%-40%的骨肉瘤组织标本出现了EGFR、HER2、HER3、HER4蛋白的过表达。进一步对ErbB家族基因扩增、蛋白过表达与骨肉瘤患者的临床生物学特性及预后进行相关性分析发现 EGFR、HER3、HER4的基因扩增与蛋白的过表达均与骨肉瘤患者的不良临床预后相关，并且与化疗反应性、远处转移密切相关。多因素相关分析证明，EGFR、HER3、HER4是骨肉瘤患者不良预后的独立预测因子。本项目支持EGFR、HER3、HER4作为骨肉瘤治疗的靶向标志物。