Genome-wide screening of loci associated with drug resistance to 5-fluorouracil-based drugs
Genome-wide screening of loci associated with drug resistance to 5-fluorouracil-based drugs
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DOI：
10.1111/j.1349-7006.2007.00424.x
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发表时间：
2007-04-01
期刊：
影响因子：
5.7
通讯作者：
Fukushima, Masakazu
中科院分区：
文献类型：
--
作者：
Ooyama, Akio;Okayama, Yoshihiro;Fukushima, Masakazu
对化疗药物的耐药性是晚期癌症患者死亡的主要原因。染色体畸变和基因表达改变是肿瘤化疗耐药的主要遗传机制。在本研究中，我们建立了一种使用 Affymetrix 10K 阵列计算 DNA 拷贝数的算法，并在 DNA 拷贝数与基于 5-氟尿嘧啶 (5-FU) 的药物（S-1、替加氟 + 尿嘧啶 [UFT]、5'-DFUR 和卡培他滨）的抗肿瘤活性之间进行了全基因组相关性分析，以使用 27 个人类癌症异种移植物筛选影响耐药性的位点。相关分析证实，与药物敏感性显着相关的单核苷酸多态性（SNP）集中在一些细胞遗传学区域（18p、17p13.2、17p12、11q14.1、11q11和11p11.12），并且我们鉴定了一些已表明与药物敏感性相关的基因。在这些区域中，胸苷酸合成酶基因 (TYMS) 位置的 18p11.32 与对 5-FU 药物的耐药性密切相关。 TYMS基因拷贝数的变化反映在TYMS表达水平上，并且与基于5-FU的药物的敏感性呈显着负相关。这些结果表明 TYMS 基因的扩增与先天耐药性相关，支持 TYMS 拷贝数可能是对氟嘧啶药物敏感性的预测标记的可能性。有必要进一步研究以阐明重要细胞遗传学区域中编码的其他基因的功能作用。这些有希望的数据表明，全面的 DNA 拷贝数分析可能有助于寻找药物反应的最佳标记。
Resistance to chemotherapeutic agents represents the chief cause of mortality in cancer patients with advanced disease. Chromosomal aberration and altered gene expression are the main genetic mechanisms of tumor chemoresistance. In this study, we have established an algorithm to calculate DNA copy number using the Affymetrix 10K array, and performed a genome-wide correlation analysis between DNA copy number and antitumor activity against 5-fluorouracil (5-FU)-based drugs (S-1, tegafur + uracil [UFT], 5'-DFUR and capecitabine) to screen for loci influencing drug resistance using 27 human cancer xenografts. A correlation analysis confirmed that the single nuceotide polymorphism ( SNP) showing significant associations with drug sensitivity were concentrated in some cytogenetic regions (18p, 17p13.2, 17p12, 11q14.1, 11q11 and 11p11.12), and we identified some genes that have been indicated their relations to drug sensitivity. Among these regions, 18p11.32 at the location of the thymidylate synthase gene (TYMS) was strongly associated with resistance to 5-FU-based drugs. A change in copy number of the TYMS gene was reflected in the TYMS expression level, and showed a significant negative correlation with sensitivity against 5-FU-based drugs. These results suggest that amplification of the TYMS gene is associated with innate resistance, supporting the possibility that TYMS copy number might be a predictive marker of drug sensitivity to fluoropyrimidines. Further study is necessary to clarify the functional roles of other genes coded in significant cytogenetic regions. These promising data suggest that a comprehensive DNA copy number analysis might aid in the quest for optimal markers of drug response.