胰腺内分泌肿瘤中PGP9.5和DAXX基因的异常改变与肿瘤良恶性的鉴别及预后判断

Pancreatic endocrine tumors are a group of uncommon tumors, the incidence and prevalence of these neoplasms were increased in recent years. Until now, it is impossible to distinguish benign from malignant form of pancreatic endocrine tumors by morphorlogy so that a subset of malignant tumors without the evidences of invasion or metastases, especially at early stage of malignancy, would be recognized as benign tumors. There is a lack of reliable biomarkers for distinguishing benignity from malignancy and, to predict the prognosis. Our previous proteomic study on insulinoma showed that protein PGP9.5 was expressed in insulinomas. In addition, it was reported that the mutation of DAXX gene was associated with the prognosis of patients with non-functional pancreatic endocrine tumors. Thus, the present research is to study if PGP9.5 and DAXX were expressed in pancreatic endocrine tumors, and whether the expression of two proteins,somatic mutation of DAXX gene and the methylation of PGP9.5 gene promoter could be used as molecular biomarkers for prognostic implication as well as for distinguishing tumor benignity from malignancy. The study includes a large series of more than 300 patients with pancreatic endocrine tumors, a suffient number of cases enable us to obtain reliable data. Finally, we will investigate the molecular mechanisms underlying the expression of PGP9.5 and DAXX gene in pancreatic endocrine tumors.

胰腺内分泌肿瘤是较为少见的肿瘤，但是近年来发病率明显上升。目前无法依靠临床病理的形态学来鉴别胰腺内分泌肿瘤的良恶性，导致部分尚未侵袭或转移的恶性胰腺内分泌肿瘤特别是早期恶性肿瘤被判断为良性，造成诊断和治疗的偏差。此外，目前尚欠缺可靠的判断预后的临床指标。因此，需要分子标志物来鉴别此类肿瘤的良恶性以及判断预后，但是目前缺乏可靠的鉴别胰腺内分泌肿瘤良恶性的分子标志物。我们以往胰岛素瘤蛋白组学的研究发现胰岛素瘤中表达PGP9.5蛋白，文献报道DAXX基因突变与无功能胰腺内分泌肿瘤的预后相关。本项目拟探讨PGP9.5和DAXX基因是否在胰腺内分泌肿瘤表达，二者蛋白的表达、DAXX外显子突变和PGP9.5甲基化可否作为分子标志物用于鉴别该类肿瘤良恶性并判断预后。本研究纳入300例以上这类少见肿瘤病人，该大样本可保证获得可靠的数据。 最后,对PGP9.5基因和DAXX基因在肿瘤表达的分子机制进行研究。

本项目按计划顺利完成。研究的主要结果是： 1、在胰腺神经内分泌肿瘤(pancreatic neuroendocrine tumors, PNETs )的组织中, PGP9.5 (又称UCH-L1)蛋白表达下降或缺失和肿瘤的大小、肿瘤转移以及分期显著正相关; 该蛋白的表达下降或缺失和患者预后显著相关, 特别是和无病生存相关, 是一个独立的判断PNETs 患者无病生存的标志物。 2、在PNETs中, DAXX蛋白的表达下降或缺失和肿瘤的的大小、肿瘤转移和复发显著正相关, 而且和肿瘤的分级、分期显著相关; 该蛋白的表达下降或缺失和患者总生存 (overall survival, OR) 和无病生存均显著相关, 但是cox 模型多因素分析发现DAXX蛋白的表达是一个独立的判断患者无病生存的标志物。3、在不同的胰腺神经内分泌肿瘤的亚类中, PGP9.5蛋白的表达率有着显著的差异, 表现在该蛋白在胰岛素瘤中的表达率显著高于非胰岛素瘤, P=7.19×10-6。. 上述这些研究结果1和2提示测定肿瘤组织中PGP9.5 (UCH-L1)蛋白和DAXX蛋白的表达有潜在的临床应用价值。