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Methylated Reprimo Cell-Free DNA as a Non-Invasive Biomarker for Gastric Cancer

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dc.contributor.authorMaturana, María
dc.contributor.authorPadilla, Oslando
dc.contributor.authorSantoro, Pablo
dc.contributor.authorAlarcón, Maria
dc.contributor.authorOlivares, Wilda
dc.contributor.authorBlanco, Alejandro
dc.contributor.authorArmisen, Ricardo
dc.contributor.authorGarrido, Marcelo
dc.contributor.authorAravena, Edmundo
dc.contributor.authorBarrientos, Carlos
dc.contributor.authorCalvo, Alfonso
dc.contributor.authorCorvalán, Alejandro
dc.date.accessioned2025-04-14T15:25:30Z
dc.date.available2025-04-14T15:25:30Z
dc.date.issued2025
dc.description.abstractRestrictions resulting from the COVID-19 pandemic abruptly reversed the slow decline of the diagnosis and mortality rates of gastric cancer (GC). This scenario highlights the importance of developing cost-effective methods for mass screening and evaluation of treatment response. In this study, we evaluated a non-invasive method based on the circulating methylated cell-free DNA (cfDNA) of Reprimo (RPRM), a tumor suppressor gene associated with the development of GC. Methylated RPRM cfDNA was analyzed in three de-identified cohorts: Cohort 1 comprised 81 participants with GC and 137 healthy donors (HDs); Cohort 2 comprised 27 participants with GC undergoing gastrectomy and/or chemotherapy analyzed at the beginning and after three months of treatment; and Cohort 3 comprised 1105 population-based participants in a secondary prevention program who underwent esophagogastroduodenal (EGD) endoscopy. This cohort includes 180 normal participants, 845 participants with premalignant conditions (692 with chronic atrophic gastritis [AG] and 153 with gastric intestinal metaplasia/low-grade dysplasia [GIM/LGD]), 21 with high-grade dysplasia/early GC [HGD/eGC], and 59 with advanced GC [aGC]). A nested case-control substudy was performed using a combination of methylated RPRM cfDNA and pepsinogens (PG)-I/II ratio. The dense CpG island of the promoter region of the RPRM gene was bisulfite sequenced and analyzed to develop a fluorescence-based real-time PCR assay (MethyLight). This assay allows the determination of the absolute number of copies of methylated RPRM cfDNA. A targeted sequence of PCR amplicon products confirmed the gastric origin of the plasma-isolated samples. In Cohort 1, the mean value of GCs (32,240.00 copies/mL) was higher than that of the HD controls (139.00 copies/mL) (p < 0.0001). After dividing this cohort into training–validation subcohorts, we identified an area under the curve of 0.764 (95% confidence interval (CI) = 0.683–0.845) in the training group. This resulted in a cut-off value of 87.37 copies/mL (sensitivity 70.0% and specificity 80.2%). The validation subcohort predicted sensitivity of 66.67% and a specificity of 83.33%. In Cohort 2 (monitoring treatment response), RPRM levels significantly decreased in responders (p = 0.0042) compared to non-responders. In Cohort 3 (population-based participants), 18.9% %, 24.1%, 30.7%, 47.0%, and 71.2% of normal, AG, GIM/LGD, HGD/eGC, and aGC participants tested positive for methylated RPRM cfDNA, respectively. Overall sensitivity and specificity in distinguishing normal/premalignant conditions vs. GC were 65.0% (95% CI 53.52% to 75.33%) and 75.9% (95% CI 73.16% to 78.49%), respectively, with an accuracy of 75.11% (95% CI 72.45% to 77.64%). Logistic regression analyses revealed an OR of 1.85 (95% CI 1.11–3.07, p = 0.02) and an odds ratio (OR) of 3.9 (95% CI 1.53–9.93, p = 0.004) for the risk of developing GIM/LGD and HGD/eGC, respectively. The combined methylated RPRM cfDNA and PG-I/II ratio reached a sensitivity of 78.9% (95% CI 54.43% to 93.95%) and specificity of 63.04% (95% CI 52.34% to 72.88%) for detecting HGD/eGC vs. three to six age- and sex-matched participants with premalignant conditions. Our results demonstrate that methylated RPRM cfDNA should be considered a direct biomarker for the non-invasive detection of GC and a predictive biomarker for treatment response.
dc.description.versionVersión Publicada
dc.identifier.citationMaturana, M.J.; Padilla, O.; Santoro, P.M.; Alarcón, M.A.; Olivares, W.; Blanco, A.; Armisen, R.; Garrido, M.; Aravena, E.; Barrientos, C.; et al. Methylated Reprimo Cell-Free DNA as a Non-Invasive Biomarker for Gastric Cancer. Int. J. Mol. Sci. 2025, 26, 3333. https://doi.org/10.3390/ ijms26073333
dc.identifier.doihttps://doi.org/10.3390/ ijms26073333
dc.identifier.urihttps://hdl.handle.net/11447/9965
dc.language.isoen
dc.subjectGastric cancer
dc.subjectBiomarkers
dc.subjectLiquid biopsy
dc.subjectNon-invasive diagnosis
dc.subjectCancer screening
dc.subjectCancer prevention
dc.subjectMethylated RPRM
dc.subjectcfDNA
dc.titleMethylated Reprimo Cell-Free DNA as a Non-Invasive Biomarker for Gastric Cancer
dc.typeArticle
dcterms.accessRightsAcceso Abierto
dcterms.sourceInternational journal of molecular sciences
dspace.entity.typePublication
relation.isAuthorOfPublicationf814e5ac-2623-4a1f-bc2b-5a1a260ee316
relation.isAuthorOfPublication.latestForDiscoveryf814e5ac-2623-4a1f-bc2b-5a1a260ee316

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