TERT Promoter Hypermethylation in Gastrointestinal Cancer: A Potential Stool Biomarker
TERT Promoter Hypermethylation in Gastrointestinal Cancer: A Potential Stool Biomarker
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胃肠癌中的 TERT 启动子高甲基化：一种潜在的粪便生物标志物
DOI：
10.1634/theoncologist.2017-0064
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发表时间：
2017-10-01
期刊：
影响因子：
5.8
通讯作者：
Xu, Dawei
中科院分区：
文献类型：
--
作者：
Liu, Li;Liu, Cheng;Xu, Dawei
背景。目前对胃肠道癌（GIC）检测的非侵入性筛查工具的需求很大，而GIC特异性标记物是用于此类目的的必要条件。已经确定，端粒酶逆转录酶基因（TERT）的诱导与端粒酶的激活对于癌症的发生/进展是必不可少的，特异性5'- c -磷酸- g -3' （CpGs）的TERT启动子甲基化异常与TERT在肿瘤发生中的诱导有关。在这里，我们分析了来自GIC患者和健康成人的粪便样本中的TERT启动子甲基化，并确定了其作为GIC检测的粪便生物标志物的价值。材料与方法。招募69名GIC患者（34名结直肠癌患者，35名胃癌患者）和62名健康成人，收集粪便样本。收集34例患者的配对肿瘤及邻近非癌组织和12例健康人的正常粘膜组织。采用焦磷酸测序法测定TERT启动子甲基化密度。我们在肿瘤组织中TERT启动子的2218位点（CpG位点1）和2210位点（CpG位点2）鉴定了两个gic特异性甲基化位点。在患者粪便中也检测到甲基化的TERT启动子CpG位点1和2，而在健康个体中仅观察到背景水平。粪便甲基化TERT启动子检测的总灵敏度达到52.2%(95%置信区间[CI]: 48.3-56.0)，特异性为90%，与其他已知的粪便甲基化标记物检测GIC相当。粪便TERT启动子甲基化和潜血（OB）联合检测可显著提高结直肠癌的敏感性和特异性（单独甲基化的曲线下面积：0.798,95% CI: 0.707-0.889，甲基化+OB: 0.920, 95% CI: 0.859-0.981, p = 0.028），但对胃癌无显著影响。这项概念验证研究表明，粪便TERT启动子甲基化分析作为非侵入性GIC筛查的额外工具是可行的。
Background. There is a high demand for noninvasive screening tools for gastrointestinal cancer (GIC) detection, and GIC-specific markers are required for such purposes. It is established that induction of the telomerase reverse transcriptase gene (TERT) coupled with telomerase activation is essential for cancer development/progression and aberrant TERT promoter methylation of specific 5'-C-phosphate-G-3' (CpGs) has been linked to TERT induction in oncogenesis. Here we analyzed TERT promoter methylation in fecal samples from GIC patients and healthy adults and determined its value as a stool biomarker for GIC detection.Materials and Methods. Sixty-nine GIC patients (34 colorectal carcinoma and 35 gastric cancer) and 62 healthy adults were recruited and fecal samples were collected. Paired tumors and adjacent non-cancerous tissues from 34 patients and normal mucosa tissues from 12 healthy individuals were collected. TERT promoter methylation density was determined using pyrosequencing.Results. We identified two GIC-specific methylation sites at 2218 (CpG site 1) and 2210 (CpG site 2) in the TERT promoter in tumor tissues. Methylated TERT promoter CpG sites 1 and 2 were also detectable in patient stool, while only background levels were observed in healthy individuals. The overall sensitivity reached 52.2% (95% confidence interval [CI]: 48.3-56.0) for fecal methylated TERT promoter assays at 90% specificity, which was comparable to other known stool methylation markers for GIC detection. The combined assays of fecal TERT promoter methylation and occult blood (OB) significantly improved sensitivity and specificity in colorectal cancer (area under curves for methylation alone: 0.798, 95% CI: 0.707-0.889 vs. methylation+OB: 0.920, 95% CI: 0.859-0.981; p = .028), but not in gastric cancer.Conclusion. This proof-of-concept study suggests the feasibility of stool TERT promoter methylation analyses as an additional tool in noninvasive GIC screening.