Laboratorio di Oncologia Translazionale, Oncologia, S. Croce General Hospital, I-12100 Cuneo, Italy.
Int J Oncol. 2010 Nov;37(5):1219-28. doi: 10.3892/ijo_00000773.
Current palliative chemotherapy (CT) regimens achieve clinical benefits in less than 50% of patients treated for metastatic gastric cancers, and long-term survivals are anecdotical. Genetic polymorphisms and differences at the level of transcription in genes involved in biological processes of drug metabolism, DNA repair and drug resistance can explain the observed individual differences in response to drugs, in survival and in different susceptibility to the toxic effects of CT. The possibility to classify patients on the basis of genetic signatures could help in choosing the CT regimen. We present herein an analysis of genetic and expression profiling of three patients affected by metastatic gastric cancer, treated with CT and alive, disease-free, at 66-82 months. Four patients with typical clinical outcome represented the control group. Expression profiling from paraffin-embedded tumor tissues was performed on an ad hoc set of genes involved in drug metabolism and resistance, DNA repair, cell cycle regulation and growth factors signalling. Genetic polymorphism analysis on DNA extracted from peripheral blood was done by pyrosequencing of genetic markers predictive of drug response. Expression analysis in long-term survivors revealed a significant upregulation of PTEN, TP63, GADD45a and MAPK1 genes. We found also an upregulation of CYP1A1, CYP3A4 and ERBB4 genes. EGF was found to be down-regulated in long-term survivors. ERCC1 C8092A polymorphism seems to be associated with survival in our set of patients. The present study shed light on a set of genes, which could have a predictive role in survival of patients with metastatic gastric tumors.
目前，转移性胃癌患者接受姑息性化疗（CT）后，不到 50%的患者能获得临床获益，长期生存者更是罕见。药物代谢、DNA 修复和耐药相关的生物学过程中基因的遗传多态性和转录水平的差异，可以解释药物反应、生存和对 CT 毒性作用的不同易感性方面的个体差异。基于遗传特征对患者进行分类的可能性有助于选择 CT 方案。我们在此报告了对 3 例接受 CT 治疗且无疾病、生存时间分别为 66-82 个月的转移性胃癌患者的基因和表达谱分析。4 例具有典型临床结局的患者作为对照组。采用专门设计的药物代谢和耐药、DNA 修复、细胞周期调节和生长因子信号相关基因的表达谱，对石蜡包埋肿瘤组织进行分析。通过对预测药物反应的遗传标记物进行焦磷酸测序，对从外周血提取的 DNA 进行遗传多态性分析。对长期生存者的表达分析显示，PTEN、TP63、GADD45a 和 MAPK1 基因显著上调。我们还发现 CYP1A1、CYP3A4 和 ERBB4 基因上调。EGF 在长期生存者中下调。在我们的患者组中，ERCC1 C8092A 多态性似乎与生存相关。本研究揭示了一组基因，这些基因可能在转移性胃肿瘤患者的生存中具有预测作用。
