Molecular profile of 5-fluorouracil pathway genes in colorectal carcinoma.
Molecular profile of 5-fluorouracil pathway genes in colorectal carcinoma.
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DOI：
10.1186/s12885-016-2826-8
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发表时间：
2016-10-12
期刊：
影响因子：
3.8
通讯作者：
Soucek P
中科院分区：
文献类型：
--
作者：
Kunicka T;Prochazka P;Krus I;Bendova P;Protivova M;Susova S;Hlavac V;Liska V;Novak P;Schneiderova M;Pitule P;Bruha J;Vycital O;Vodicka P;Soucek P
本研究探讨了5-氟尿嘧啶（5-FU）通路主要基因在大肠癌患者预后中的作用。使用来自151例患者的配对肿瘤和邻近粘膜组织样本的测试集和两个验证集，通过定量实时PCR和高分辨率熔化分析的DNA甲基化分析，对15个5-FU通路基因进行转录分析。肿瘤内分子谱与患者临床资料相关。两种最相关的候选标记物的蛋白水平通过免疫印迹法进行评估。在患者的测试和验证组中，与邻近粘膜相比，肿瘤中发现DPYD下调，PPAT、UMPS、RRM2和SLC29A1转录本上调。低RRM2转录水平与测试组对一线姑息性5-FU化疗的不良反应显著相关，与验证组患者的无病间隔较差相关，无论5-FU治疗如何。在肿瘤和邻近粘膜中，UPP2被强烈甲基化，而其转录物缺失。肿瘤组织中DPYS甲基化水平明显高于邻近粘膜样本。肿瘤内UPB1甲基化水平低是患者无病间期差的预后因素（P = 0.0002）。其余研究的5-FU基因在肿瘤或邻近粘膜中未甲基化。观察到的几种5-FU激活基因的过表达和DPYD下调推断化疗naïve结直肠肿瘤具有有利的5-FU治疗基因表达谱。低RRM2转录和UPB1甲基化水平是结直肠癌患者预后不良的单独因素，需要进一步研究。本文的在线版本（doi:10.1186/s12885-016-2826-8）包含补充材料，仅供授权用户使用。
This study addresses involvement of major 5-fluorouracil (5-FU) pathway genes in the prognosis of colorectal carcinoma patients. Testing set and two validation sets comprising paired tumor and adjacent mucosa tissue samples from 151 patients were used for transcript profiling of 15 5-FU pathway genes by quantitative real-time PCR and DNA methylation profiling by high resolution melting analysis. Intratumoral molecular profiles were correlated with clinical data of patients. Protein levels of two most relevant candidate markers were assessed by immunoblotting. Downregulation of DPYD and upregulation of PPAT, UMPS, RRM2, and SLC29A1 transcripts were found in tumors compared to adjacent mucosa in testing and validation sets of patients. Low RRM2 transcript level significantly associated with poor response to the first-line palliative 5-FU-based chemotherapy in the testing set and with poor disease-free interval of patients in the validation set irrespective of 5-FU treatment. UPP2 was strongly methylated while its transcript absent in both tumors and adjacent mucosa. DPYS methylation level was significantly higher in tumor tissues compared to adjacent mucosa samples. Low intratumoral level of UPB1 methylation was prognostic for poor disease-free interval of the patients (P = 0.0002). The rest of the studied 5-FU genes were not methylated in tumors or adjacent mucosa. The observed overexpression of several 5-FU activating genes and DPYD downregulation deduce that chemotherapy naïve colorectal tumors share favorable gene expression profile for 5-FU therapy. Low RRM2 transcript and UPB1 methylation levels present separate poor prognosis factors for colorectal carcinoma patients and should be further investigated. The online version of this article (doi:10.1186/s12885-016-2826-8) contains supplementary material, which is available to authorized users.
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