Background: Grade 2 and 3 and dedifferentiated chondrosarcomas (CS) are frequently associated with isocitrate dehydrogenase (IDH) mutations and often exhibit a poor clinical outcome. Treatment is limited mainly to surgery. DefiningIDHstatus (wild type (WT) and mutant) and the associated transcriptome may prove useful in determining other therapeutic options in these neoplasms. Methods: Formalin-fixed paraffin-embedded material from 69 primary and recurrent grade 2, 3 and dedifferentiated CS was obtained. DNA sequencing forIDH1andIDH2mutations (n= 47) and RNA sequencing via Nextseq 2000 (n= 14) were performed. Differentially expressed genes (DEGs) were identified and used to predict aberrant biological pathways with Ingenuity Pathway Analysis (IPA) software (Qiagen). Gene Set Enrichment Analyses (GSEA) using subsets C3, C5 and C7 were performed. Differentially expressed genes were validated by immunohistochemistry. Outcome analysis was performed using the Wilcoxon test. Results: A set of 69 CS (28 females, 41 males), average age 65, distributed among femur, pelvis, humerus, and chest wall were identified from available clinical material. After further selection based on availableIDHstatus, we evaluated 15IDHWT and 32IDHmutant tumors as part of this dataset. Out of 15IDHWT tumors, 7 involved the chest wall/scapula, while 1 of 32 mutants arose in the scapula. There were far more genes overexpressed inIDHWT tumors compared toIDHmutant tumors. Furthermore,IDHWT andIDHmutant tumors were transcriptomically distinct in the IPA and GSEA, withIDHmutant tumors showing increased activity in methylation pathways and endochondral ossification, whileIDHWT tumors showed more activity in normal matrix development pathways. Validation immunohistochemistry demonstrated expression of WT1 and AR inIDHWT tumors, but not inIDHmutants. SATB2 was expressed inIDHmutant tumors and not in WT tumors. Outcome analysis revealed differences in overall survival between mutant and WT tumors (p= 0.04), dedifferentiated mutant and higher-grade (2, 3) mutant tumors (p= 0.03), and dedifferentiated mutant and higher-grade (2, 3) WT tumors (p= 0.03). The longest survival times were observed in patients with higher-grade WT tumors, while patients with dedifferentiated mutant tumors showed the lowest survival. Generally, patients withIDHWT tumors displayed longer survival in both the higher-grade and dedifferentiated groups. Conclusions: Grade 2, 3 and dedifferentiated chondrosarcomas are further characterized byIDHstatus, which in turn informs transcriptomic phenotype and overall survival. The transcriptome is distinct depending onIDHstatus, and implies different treatment targets.
背景：2级、3级及去分化软骨肉瘤常伴有异柠檬酸脱氢酶突变，且临床预后通常较差。目前治疗手段主要局限于手术。明确IDH状态（野生型与突变型）及其相关转录组特征，可能有助于为这类肿瘤探索其他治疗选择。 方法：研究收集了69例原发及复发性2级、3级及去分化软骨肉瘤的石蜡包埋组织样本。对其中47例进行了IDH1和IDH2基因突变测序，14例通过Nextseq 2000平台进行RNA测序。利用IPA软件识别差异表达基因并预测异常生物学通路，同时采用C3、C5和C7亚集进行基因集富集分析。通过免疫组化验证差异表达基因，并运用Wilcoxon检验进行预后分析。 结果：从现有临床资料中确认了69例软骨肉瘤（女性28例，男性41例），平均年龄65岁，肿瘤分布于股骨、骨盆、肱骨及胸壁。根据IDH状态进一步筛选后，本研究数据集包含15例IDH野生型与32例IDH突变型肿瘤。15例野生型肿瘤中有7例位于胸壁/肩胛骨，而32例突变型中仅1例发生于肩胛骨。与突变型相比，野生型肿瘤存在更多过表达基因。IPA与GSEA分析显示两类肿瘤具有显著差异的转录组特征：突变型肿瘤在甲基化通路及软骨内骨化过程中活性增强，而野生型肿瘤在正常基质发育通路中更为活跃。免疫组化验证显示WT1与AR蛋白在野生型肿瘤中表达，而在突变型中不表达；SATB2则在突变型肿瘤中特异性表达。预后分析显示：突变型与野生型肿瘤的总生存期存在差异（p=0.04），去分化突变型与高级别（2、3级）突变型肿瘤（p=0.03），以及去分化突变型与高级别野生型肿瘤（p=0.03）之间也存在显著差异。高级别野生型肿瘤患者生存期最长，而去分化突变型患者生存期最短。总体而言，在高级别组与去分化组中，IDH野生型患者均表现出更长的生存期。 结论：IDH状态可进一步表征2级、3级及去分化软骨肉瘤的生物学特性，该状态与转录组表型及总生存期密切相关。不同IDH状态对应独特的转录组特征，提示其潜在治疗靶点存在差异。
肿瘤(癌症)患者之家