El-Shakankiry Nayera H, Mossallam Ghada I
The Department of Clinical Pathology, National Cancer Institute, Cairo University, Egypt.
J Egypt Natl Canc Inst. 2006 Sep;18(3):227-32.
Hypermethylation within the promoters of selected genes is an epigenetic pathway that appears to be especially common in all types of human haematopoeitic neoplasms. It is usually associated with inactivation of the involved genes, and can be reversed using demethylating agents. The aim of this study is to evaluate the frequency of p15 and E-cadherin promoter methylation in Egyptian acute myeloid leukemia (AML) patients in an attempt to identify a subset of patients who might be candidates for demethylating agents as a form of targeted therapy either as a primary or as an adjunct to current standard induction and post-remission regimens.
In the present work we have studied tumor-associated aberrant p15 and E-cadherin promotor methylation in 59 newly diagnosed acute myeloid leukemia (AML) patients using methylation specific PCR.
Aberrant p15 promoter methylation was detected in 49% (29/59) of the patients. In 4 of these patients, no DNA could be amplified by the p15 unmethylated reaction showing a complete methylation of both alleles in the examined region. In the remaining 25 cases both methylated and unmethylated DNA could be amplified. Aberrant methylation of E-cadherin was detected in 63% (37/59) of the cases. In all of these cases both the methylated and the unmethylated alleles were amplified denoting partial methylation of the examined region. Concomitant methylation of p15 and E-cadherin was detected in 40% (23/59) of all the cases tested, while in 27% (16/59) of the cases both genes were not methylated.
These results demonstrate that p15 and E-cadherin promoter methylation are frequent events in Egyptian AML and provide an impetus for larger studies to define the extent and pattern of methylation in the various subgroups of AML. Methylation studies, therefore, represent a novel additional tool to define the subset of patients who might benefit from demethylating agents,thus providing the molecular basis for targeted therapeutic approaches and better designing of risk-adapted therapy.
特定基因启动子区域的高甲基化是一种表观遗传途径，在各类人类血液系统肿瘤中似乎尤为常见。它通常与相关基因的失活有关，并且可以使用去甲基化剂使其逆转。本研究的目的是评估埃及急性髓系白血病（AML）患者中p15和E-钙黏蛋白启动子甲基化的频率，以试图确定可能作为靶向治疗候选者的患者亚群，这种靶向治疗可以是作为主要治疗手段，或者作为当前标准诱导缓解和缓解后治疗方案的辅助治疗。
在本研究中，我们使用甲基化特异性PCR研究了59例新诊断的急性髓系白血病（AML）患者中与肿瘤相关的异常p15和E-钙黏蛋白启动子甲基化情况。
49%（29/59）的患者检测到异常的p15启动子甲基化。在其中4例患者中，p15未甲基化反应无法扩增出DNA，表明所检测区域的两个等位基因均完全甲基化。在其余25例中，甲基化和未甲基化的DNA均可扩增。63%（37/59）的病例检测到E-钙黏蛋白的异常甲基化。在所有这些病例中，甲基化和未甲基化的等位基因均被扩增，表明所检测区域存在部分甲基化。在所有检测病例中，40%（23/59）的病例同时存在p15和E-钙黏蛋白的甲基化，而27%（16/59）的病例两个基因均未甲基化。
这些结果表明，p15和E-钙黏蛋白启动子甲基化在埃及AML患者中很常见，并为开展更大规模研究以确定AML各亚组中甲基化的程度和模式提供了动力。因此，甲基化研究是一种新的额外工具，可用于确定可能从去甲基化剂中获益的患者亚群，从而为靶向治疗方法提供分子基础，并更好地设计风险适应性治疗。
