Kosumi Keisuke, Baba Yoshifumi, Ishimoto Takatsugu, Harada Kazuto, Miyake Keisuke, Izumi Daisuke, Tokunaga Ryuma, Murata Asuka, Eto Kojiro, Sugihara Hidetaka, Shigaki Hironobu, Iwagami Shiro, Sakamoto Yasuo, Miyamoto Yuji, Yoshida Naoya, Watanabe Masayuki, Komohara Yoshihiro, Takeya Motohiro, Baba Hideo
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
Med Oncol. 2015 Apr;32(4):117. doi: 10.1007/s12032-015-0571-5. Epub 2015 Mar 18.
The DNA methylation alterations occurring in human cancers have two types: global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Recently, to assess global DNA methylation, long interspersed nucleotide element 1 (LINE-1) retrotransposons, constituting a substantial portion of the human genome, attracts much attention. The aim of the current study was to clarify the significance of LINE-1 methylation level for epigenetic field defects and the relationships among LINE-1 methylation level in gastric mucosae, clinical and pathological features, including infection by Helicobacter pylori (H. pylori), a bacterium implicated in gastric cancer. By bisulfite-PCR pyrosequencing, we quantified the LINE-1 methylation levels in noncancerous gastric mucosae and cancer tissues from 87 gastric cancer patients, in gastric mucosae from 17 autopsied individuals without gastric cancers and in 20 gastric fresh frozen samples from non-gastric cancer patients. LINE-1 methylation in the noncancerous gastric mucosae of gastric cancer patients was significantly higher than in cancer tissues (P = 0.0006), but significantly lower than in the gastric mucosae of the autopsied individuals (P = 0.026), suggesting the formation of epigenetic field defect in noncancerous gastric mucosae. Moreover, LINE-1 hypomethylation of noncancerous gastric mucosae in gastric cancer patients significantly correlated with H. pylori infection (P = 0.037). We prospectively confirmed the similar result in 20 non-gastric cancer patients (P = 0.010). LINE-1 hypomethylation of gastric mucosae significantly correlated with H. pylori infection, supporting the potential of LINE-1 methylation level as a surrogate marker of epigenetic field defects for gastric cancer cancerization, particularly induced by H. pylori.
人类癌症中发生的DNA甲基化改变有两种类型：全基因组DNA低甲基化和位点特异性CpG岛启动子高甲基化。最近，为了评估全基因组DNA甲基化，长散在核元件1（LINE-1）逆转座子（构成人类基因组的很大一部分）引起了广泛关注。本研究的目的是阐明LINE-1甲基化水平对表观遗传学领域缺陷的意义，以及胃癌黏膜中LINE-1甲基化水平与临床和病理特征（包括幽门螺杆菌感染，一种与胃癌有关的细菌）之间的关系。通过亚硫酸氢盐PCR焦磷酸测序，我们对87例胃癌患者的非癌性胃黏膜和癌组织、17例无胃癌的尸检个体的胃黏膜以及20例非胃癌患者的胃新鲜冷冻样本中的LINE-1甲基化水平进行了定量。胃癌患者非癌性胃黏膜中的LINE-1甲基化显著高于癌组织（P = 0.0006），但显著低于尸检个体的胃黏膜（P = 0.026），这表明非癌性胃黏膜中存在表观遗传学领域缺陷。此外，胃癌患者非癌性胃黏膜的LINE-1低甲基化与幽门螺杆菌感染显著相关（P = 0.037）。我们在20例非胃癌患者中前瞻性地证实了类似结果（P = 0.010）。胃黏膜的LINE-1低甲基化与幽门螺杆菌感染显著相关，这支持了LINE-1甲基化水平作为胃癌致癌表观遗传学领域缺陷替代标志物的潜力，特别是由幽门螺杆菌诱导的。
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