Prognostic significance of drug-regulated genes in high-grade osteosarcoma
Prognostic significance of drug-regulated genes in high-grade osteosarcoma
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DOI：
10.1038/modpathol.3800937
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发表时间：
2007-10-01
期刊：
影响因子：
7.5
通讯作者：
Zahlten-Hinguranage, Anita
中科院分区：
文献类型：
--
作者：
Fellenberg, Joerg;Bernd, Ludger;Zahlten-Hinguranage, Anita
约25-45%的高级别骨肉瘤患者对化疗反应不良，复发和转移的风险增加。因此，本研究的目的是评估八个先前确定的药物调节候选基因对骨肉瘤治疗结果的预后价值。对35例经福尔马林固定、石蜡包埋、激光显微解剖的骨肉瘤活检组织中8个候选基因的表达进行了分析。在单因素和多因素分析中，通过基因表达与治疗结果、总生存期和无事件生存期的相关性来评估这些基因的预后价值。单因素分析发现，MALAT-1、IMPDH2、FTL和RHOA的表达与化疗反应显著相关。四种基因的表达在不良反应组中均有所增加。多因素分析显示，IMPDH2仍具有独立的预后价值（P = 0.025）。关于患者的总生存期，我们观察到FTL、PHB、ATAD2、ACTN1和RRM2的表达以及血清乳酸脱氢酶水平与患者的总生存期有显著相关性。在这些基因高表达的患者亚组和乳酸脱氢酶水平升高的患者亚组中，平均总生存率分别降低1.7倍、1.9倍、2.2倍、2.4倍、1.5倍和4.5倍。在多因素分析中，除RRM2外，所有基因和乳酸脱氢酶血清水平均保持显著性。此外，FTL、ATAD2和IMPDH2高表达患者亚组的无事件生存率显著降低（分别为1.8倍、6.3倍和2.4倍）。这些数据表明，鉴定的基因是预测骨肉瘤治疗结果的有价值的标记。特别是IMPDH2和FTL是将骨肉瘤患者分层为低危组和高危组的有希望的候选者。由于它们参与药物作用，这些基因可能进一步成为药物敏感性调节的潜在靶点。
About 25-45% of patients with high-grade osteosarcoma poorly respond to chemotherapy with an increased risk of relapse and the development of metastasis. Therefore, the aim of this study was the evaluation of the prognostic value of eight previously identified drug-regulated candidate genes on osteosarcoma therapy outcome. Gene expression of 8 candidate genes was analyzed in 35 formalin-fixed, paraffin-embedded, laser-microdissected osteosarcoma biopsies. The prognostic value of these genes was evaluated by the correlation of gene expression with therapy outcome, overall survival and event-free survival in univariate and multivariate analysis. Upon univariate analysis, the expression of MALAT-1, IMPDH2, FTL and RHOA significantly correlated with response to chemotherapy. Expression of all four genes was increased in the poor responder group. Upon multivariate analysis, IMPDH2 maintained its independent prognostic value (P = 0.025). Concerning the overall survival of the patients, we observed a significant association with the expression of FTL, PHB, ATAD2, ACTN1 and RRM2 as well as lactate dehydrogenase serum levels. In the subgroups of patients with high expression of these genes and those with elevated lactate dehydrogenase levels, the mean overall survival was decreased 1.7-, 1.9-, 2.2-, 2.4-, 1.5-and 4.5-fold, respectively. Except RRM2, all genes and lactate dehydrogenase serum levels remained significant in the multivariate analysis. In addition, the event-free survival was significantly decreased in the subgroups of patients with high FTL, ATAD2 and IMPDH2 expression (1.8-, 6.3 and 2.4-fold, respectively). These data demonstrate that among the identified genes are valuable markers for the prediction of osteosarcoma therapy outcome. Especially IMPDH2 and FTL are promising candidates for the stratification of osteosarcoma patients into low- and high-risk groups. Owing to their involvement in drug action these genes may further be potential targets for the modulation of drug sensitivity.