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Παρασκευή 28 Ιουλίου 2017

TERT Promoter Hypermethylation in Gastrointestinal Cancer: A Potential Stool Biomarker

AbstractBackground.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 −218 (CpG site 1) and −210 (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. The OncologistImplications for Practice.Induction of telomerase reverse transcriptase (TERT) expression coupled with telomerase activation is essential for cancer development/progression, while aberrant TERT promoter methylation has been linked to TERT induction in oncogenesis. We identified two cancer‐specific methylation sites (CpG1 and 2) in the TERT promoter in tumors from GIC patients. Methylated TERT promoter CpG sites 1 and 2 were detectable in patient stool, while only background levels were observed in healthy individuals. The sensitivity and specificity was comparable to other known stool methylation markers for GIC detection. This proof‐of‐concept study suggests the feasibility of stool TERT promoter methylation analyses for noninvasive screening of GIC.

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