Swets Marloes, Zaalberg Anniek, Boot Arnoud, van Wezel Tom, Frouws Martine A, Bastiaannet Esther, Gelderblom Hans, van de Velde Cornelis J H, Kuppen Peter J K
Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Department of Clinical Oncology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Int J Mol Sci. 2016 Dec 27;18(1):36. doi: 10.3390/ijms18010036.
Genome-wide DNA hypomethylation is associated with a worse prognosis in early-stage colorectal cancer. To measure genome-wide DNA methylation levels, long interspersed nucleotide element (LINE-1) repeats are used as a surrogate marker. Cohort studies on the clinical impact of genome-wide DNA methylation level in patients with only early-stage colon cancer, are currently lacking. This study aimed to investigate the prognostic value of LINE-1 methylation in a stage II colon cancer cohort ( = 164). Manual needle microdissection of tumor areas was performed on formalin-fixed paraffin-embedded tumor tissue sections followed by DNA extraction. Bisulfite converted DNA was used to assess tumor LINE-1 methylation level by qPCR. Patients with LINE-1 hypomethylated tumors had a significantly worse overall survival compared to patients with a higher level of LINE-1 tumor DNA methylation (HR 1.68, 95% CI 1.03-2.75; = 0.04). This effect was more prominent in patients aged over 65 years (HR 2.00, 95% CI 1.13-3.52; = 0.02), although the test for age interaction was not significant. No significant effect on recurrence-free survival was observed. Based on these results, tumor LINE-1 hypomethylation is associated with a worse overall survival in stage II colon cancer. Whether the origin of this causation is cancer-specific or age-related can be debated.
全基因组DNA低甲基化与早期结直肠癌预后较差相关。为了测量全基因组DNA甲基化水平，长散在核元件（LINE-1）重复序列被用作替代标志物。目前缺乏关于仅患有早期结肠癌患者的全基因组DNA甲基化水平临床影响的队列研究。本研究旨在调查LINE-1甲基化在II期结肠癌队列（n = 164）中的预后价值。对福尔马林固定石蜡包埋的肿瘤组织切片进行肿瘤区域的手动针吸显微切割，随后进行DNA提取。亚硫酸氢盐转化的DNA用于通过qPCR评估肿瘤LINE-1甲基化水平。与LINE-1肿瘤DNA甲基化水平较高的患者相比，LINE-1低甲基化肿瘤患者的总生存期明显更差（HR 1.68，95%CI 1.03 - 2.75；P = 0.04）。这种效应在65岁以上的患者中更为显著（HR 2.00，95%CI 1.13 - 3.52；P = 0.02），尽管年龄交互作用检验不显著。未观察到对无复发生存期的显著影响。基于这些结果，肿瘤LINE-1低甲基化与II期结肠癌患者较差的总生存期相关。这种因果关系的起源是癌症特异性的还是与年龄相关的，尚存在争议。
