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Methylated Reprimo Cell-Free DNA as a Non-Invasive Biomarker for Gastric Cancer
(MDPI AG, 2025-04-03)
María José Maturana
;
Oslando Padilla
;
Pablo M. Santoro
;
Maria Alejandra Alarcón
;
Wilda Olivares
Restrictions 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 a 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.
1Scopus© Citations 4
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A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer
(2021)
Miguel Cordova-Delgado
;
María Loreto Bravo
;
Elisa Cumsille
;
Charlotte N. Hill
;
Matías Muñoz-Medel
<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3–4 toxicity.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in <jats:italic>GSTP1</jats:italic>, <jats:italic>ERCC2</jats:italic>, <jats:italic>ERCC1</jats:italic>, <jats:italic>TP53</jats:italic>, <jats:italic>UMPS</jats:italic>, <jats:italic>SHMT1</jats:italic>, <jats:italic>MTHFR</jats:italic>, <jats:italic>ABCC2</jats:italic> and <jats:italic>DPYD</jats:italic> were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Reported grade ≤ 2 and 3–4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected <jats:italic>DPYD</jats:italic> SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70–10.95, <jats:italic>p</jats:italic> = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19–1.08; <jats:italic>p</jats:italic> = 0.071). Combination of paired SNPs demonstrated significant associations in <jats:italic>DPYD</jats:italic> (rs1801265), <jats:italic>UMPS</jats:italic> (rs1801019), <jats:italic>ABCC2</jats:italic> (rs717620) and <jats:italic>SHMT1</jats:italic> (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs <jats:italic>DPYD</jats:italic> (rs1801265) + <jats:italic>ABCC2</jats:italic> (rs717620), and <jats:italic>DPYD</jats:italic> (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusion</jats:title> <jats:p>Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.</jats:p> </jats:sec>
Scopus© Citations 11 3
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Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer
(2020)
Kohei Shitara
;
Eric Van Cutsem
;
Yung-Jue Bang
;
Charles Fuchs
;
Lucjan Wyrwicz
37Scopus© Citations 899

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