Epigenetics as a mechanism driving polygenic clinical drug resistance.
Epigenetics as a mechanism driving polygenic clinical drug resistance.
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DOI：
10.1038/sj.bjc.6603024
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发表时间：
2006-04-24
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
位于基因启动子或其附近的CpG岛的异常甲基化与肿瘤发展过程中基因表达的失活有关。越来越多的人认识到，这种突变可能比基因突变发生的频率高得多，因此在肿瘤进展或获得抗癌药物耐药性期间对细胞亚群的选择有更大的影响。尽管基于实验室的抗癌药物获得性耐药模型倾向于关注特定基因或生化途径，但这种“一个基因：一个结果”模型可能过于简化了癌症患者对治疗的获得性耐药。相反，临床耐药可能是由于大量基因表达的变化，这些基因对化学敏感性有累积影响。在肿瘤发展和耐药获得过程中以非随机方式发生的多基因CpG岛甲基化异常提供了一种机制，可以同时影响多个基因的表达，从而导致多基因临床耐药。如果多个基因同时的表观遗传调控确实是患者肿瘤对抗癌药物获得性耐药背后的主要驱动力，那么这对于化疗后临床结果的生物标志物研究以及旨在规避或调节耐药的临床方法具有重要意义。
Aberrant methylation of CpG islands located at or near gene promoters is associated with inactivation of gene expression during tumour development. It is increasingly recognised that such epimutations may occur at a much higher frequency than gene mutation and therefore have a greater impact on selection of subpopulations of cells during tumour progression or acquisition of resistance to anticancer drugs. Although laboratory-based models of acquired resistance to anticancer agents tend to focus on specific genes or biochemical pathways, such ‘one gene : one outcome’ models may be an oversimplification of acquired resistance to treatment of cancer patients. Instead, clinical drug resistance may be due to changes in expression of a large number of genes that have a cumulative impact on chemosensitivity. Aberrant CpG island methylation of multiple genes occurring in a nonrandom manner during tumour development and during the acquisition of drug resistance provides a mechanism whereby expression of multiple genes could be affected simultaneously resulting in polygenic clinical drug resistance. If simultaneous epigenetic regulation of multiple genes is indeed a major driving force behind acquired resistance of patients' tumour to anticancer agents, this has important implications for biomarker studies of clinical outcome following chemotherapy and for clinical approaches designed to circumvent or modulate drug resistance.
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DOI：
10.1073/pnas.93.18.9821
发表时间：
1996-09-03
影响因子：
11.1
作者：
Herman, JG;Graff, JR;Baylin, SB
通讯作者：
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影响因子：
3.5
作者：
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通讯作者：
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影响因子：
11.5
作者：
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通讯作者：
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影响因子：
30.8
作者：
Cameron, EE;Bachman, KE;Baylin, SB
通讯作者：
Baylin, SB
影响因子：
9.8
作者：
Bair E;Tibshirani R
通讯作者：
Tibshirani R