DNA methylation of apoptosis genes in rectal cancer predicts patient survival and tumor recurrence.
DNA methylation of apoptosis genes in rectal cancer predicts patient survival and tumor recurrence.
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DOI：
10.1007/s10495-014-1022-z
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发表时间：
2014-11
期刊：
影响因子：
7.2
通讯作者：
Kuppen, Peter J. K.
中科院分区：
文献类型：
--
作者：
Benard, Anne;Zeestraten, Eliane C. M.;Goossens-Beumer, Ines J.;Putter, Hein;van de Velde, Cornelis J. H.;Hoon, Dave S. B.;Kuppen, Peter J. K.
作为肿瘤生长和进展的标志之一，细胞凋亡通路的失控已被证明对直肠癌的肿瘤复发有预后价值。为了开发与临床相关的生物标志物，我们利用甲基化敏感的限制性内切酶对直肠癌患者关键细胞凋亡基因启动子区的甲基化状态进行了研究。从49例I-III期直肠癌患者和10例正常直肠组织新鲜冰冻肿瘤组织中提取DNA。这项初步研究的结果在88例III期肿瘤组织和18例正常直肠组织中得到了验证。我们发现固有的凋亡途径基因Apaf1、Bcl2和P53的甲基化与肿瘤的凋亡状态(M30)相关。这三个基因的联合生存分析基于显示高甲基化的基因数量(均为低、1高、2高或全部高)，显示随着甲基化标记数量的增加，患者的生存期和无复发期更短。多因素分析显示总生存率(P=0.004；HR=0.28(0.09~0.83))、肿瘤特异性生存率(P=0.004；HR=0.13(0.03~0.67))和无远处复发生存率(P=0.001；HR=0.22(0.05~0.94))有显著差异。所有标记物甲基化程度较低的患者存活时间最短，正如预期的那样，这与高凋亡率(M30)相关，但也与高增殖(Ki-67)相关。对细胞凋亡基因的表观遗传调控的研究有助于更深入地了解直肠癌的发生过程，并有助于进一步完善针对个体患者的治疗方案。
Deregulation of the apoptotic pathway, one of the hallmarks of tumor growth and -progression, has been shown to have prognostic value for tumor recurrence in rectal cancer. In order to develop clinically relevant bio-markers, we studied the methylation status of promoter regions of key apoptosis genes in rectal cancer patients, using methylation-sensitive restriction enzymes. DNA was extracted from fresh-frozen tumor tissues of 49 stage I-III rectal cancer patients and 10 normal rectal tissues. The results of this pilot study were validated in 88 stage III tumor tissues and 18 normal rectal tissues. We found that methylation of the intrinsic apoptotic pathway genes Apaf1, Bcl2 and p53 correlated with the apoptotic status (M30) of the tumor. Combined survival analyses of these three genes, based on the number of genes showing high methylation (all low, 1 high, 2 high or all high), showed shorter patient survival and recurrence-free periods with an increasing number of methylated markers. Multivariate analyses showed significant differences for overall survival (p = 0.01; HR = 0.28 (0.09–0.83)), cancer-specific survival (p = 0.004; HR = 0.13 (0.03–0.67)) and distant recurrence-free survival (p = 0.001; HR = 0.22(0.05–0.94)). The shortest survival was observed for patients showing low methylation of all markers, which—as was expected—correlated with high apoptosis (M30), but also with high proliferation (Ki-67). The study of epigenetic regulation of apoptosis genes provides more insight in the tumorigenic process in rectal cancer and might be helpful in further refining treatment regimens for individual patients.
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DOI：
10.1080/110241599750006613
发表时间：
1999-05-01
期刊：
EUROPEAN JOURNAL OF SURGERY
影响因子：
--
作者：
Kapiteijn, E;Kranenbarg, EK;van de Velde, CJH
通讯作者：
van de Velde, CJH
影响因子：
2.5
作者：
Kim, YH;Lee, JH;Choi, KW
通讯作者：
Choi, KW
影响因子：
7
作者：
Hinoue, Toshinori;Weisenberger, Daniel J.;Laird, Peter W.
通讯作者：
Laird, Peter W.
影响因子：
158.5
作者：
Kapiteijn, E;Marijnen, CAM;van de Velde, CJH
通讯作者：
van de Velde, CJH
影响因子：
8.4
作者：
Lange, M. M.;Marijnen, C. A. M.;van de Velde, C. J. H.
通讯作者：
van de Velde, C. J. H.