Fourth Department of Internal Medicine, Attikon University Hospital, Athens, Greece
First Propaedeutic Department of Surgery, AHEPA Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
Anticancer Res. 2014 Sep;34(9):4949-62.
Several studies have recently indicated the prognostic or predictive role of several biomarkers in colorectal cancer. We sought to investigate the prognostic value of prostaglandin synthase 2 (PTGS2), cyclooxygenase 2 (COX2), thymidylate synthetase (TYMS), thymidine phosphorylase (TYMP), dihydropyrimidine dehydrogenase (DPYD) and topoisomerase I (TOPO1) in colorectal cancer patients treated with 5-FU-based regimens, such as De Gramont and FOLFOX in the adjuvant setting.
In total, 96 formalin-fixed paraffin-embedded and 30 fresh-frozen tumor tissue samples were evaluated using immunohistochemistry, quantitative reverse transcription-polymerase chain reaction and microarray gene expression profiling, respectively.
The majority of tumors exhibited protein overexpression of COX2 (69%), TYMS (75%) and TOPO1 (75%). There was a significant association of TYMP protein expression with T classification, gender and stage (p=0.040, p=0.041 and p=0.011, respectively). TOPO1 protein expression was correlated with TOPO1 mRNA expression and was positively associated with stage (p=0.002) and lymph node infiltration (p=0.004). In univariate analysis, patients with high TYMS mRNA expression were shown to have a significantly lower risk for progression and death (Wald's p=0.030 and p=0.015, respectively). However, in multivariate analysis, only a trend for decreased risk for death was shown in patients with high TYMS mRNA expression (Wald's p=0.083), while patients with high PTGS2 mRNA expression had a trend for lower risk for progression (p=0.064). Using supervised hierarchical clustering, based on the expression in fresh-frozen tumor tissue of PTGS2, TYMS, TYMP and DPYD, our 30 patients were separated into two clusters. One of the clusters was enriched with patients with infiltrated lymph nodes (p<0.05), suggesting that these genes might have an impact on the tumor's ability to metastasize.
These findings indicate a possible prognostic role of TYMS mRNA expression and highlight a cluster of genes associated with nodal metastases that warrant further investigation in a larger cohort of patients with colorectal cancer treated with 5-FU-based adjuvant chemotherapy.
最近有几项研究表明，几种生物标志物在结直肠癌中具有预后或预测作用。我们试图研究前列腺素合酶 2（PTGS2）、环氧化酶 2（COX2）、胸苷酸合成酶（TYMS）、胸苷磷酸化酶（TYMP）、二氢嘧啶脱氢酶（DPYD）和拓扑异构酶 I（TOPO1）在接受 5-FU 为基础的方案（如 De Gramont 和 FOLFOX）治疗的结直肠癌患者中的预后价值。
共评估了 96 例福尔马林固定石蜡包埋和 30 例新鲜冷冻肿瘤组织样本，分别采用免疫组织化学、定量逆转录-聚合酶链反应和微阵列基因表达谱分析。
大多数肿瘤显示 COX2（69%）、TYMS（75%）和 TOPO1（75%）蛋白过表达。TYMP 蛋白表达与 T 分类、性别和分期显著相关（p=0.040，p=0.041 和 p=0.011）。TOPO1 蛋白表达与 TOPO1 mRNA 表达相关，与分期（p=0.002）和淋巴结浸润（p=0.004）呈正相关。在单因素分析中，高 TYMS mRNA 表达的患者疾病进展和死亡的风险显著降低（Wald's p=0.030 和 p=0.015）。然而，在多因素分析中，仅在高 TYMS mRNA 表达的患者中显示出死亡风险降低的趋势（Wald's p=0.083），而高 PTGS2 mRNA 表达的患者疾病进展的风险降低呈趋势（p=0.064）。基于新鲜冷冻肿瘤组织中 PTGS2、TYMS、TYMP 和 DPYD 的表达，使用监督层次聚类，我们的 30 名患者被分为两个聚类。其中一个聚类富含浸润性淋巴结的患者（p<0.05），这表明这些基因可能对肿瘤转移能力有影响。
这些发现表明 TYMS mRNA 表达具有可能的预后作用，并突出了一组与淋巴结转移相关的基因，这些基因值得在接受 5-FU 为基础的辅助化疗的更大队列的结直肠癌患者中进一步研究。
