Browsing by Author "Owen, Gareth I."

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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) Cordova-Delgado, Miguel; Bravo, María Loreto; Cumsille, Elisa; Hill, Charlotte N.; Muñoz-Medel, Matías; Pinto, Mauricio P.; Retamal, Ignacio N.; Lavanderos, María A.; Miquel, Juan Francisco; Rodriguez-Fernandez, Maria; Liao, Yuwei; Li, Zhiguang; Corvalán, Alejandro H.; Armisén, Ricardo; Garrido, Marcelo; Quiñones, Luis A.; Owen, Gareth I.
    Background: 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. Methods: 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 GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms. Results: Reported grade ≤ 2 and 3–4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70–10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19–1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity. Conclusion: Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.
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    A Molecular Stratification of Chilean Gastric Cancer Patients with Potential Clinical Applicability
    (MDPI, Basel Sz., 2020) Pinto, Mauricio; Córdova-Delgado, Miguel; Retamal, Ignacio; Muñoz-Medel, Matías; Bravo, Loreto; Durán, Doris; Villanueva, Francisco; Sánchez, César; Acevedo, Francisco; Mondaca, Sebastián; Érica, Koch; Ibáñez, Carolina; Galindo, Héctor; Madrid, Jorge; Nervi, Bruno; Peña, José; Torres, Javiera; Garrido, Marcelo; Owen, Gareth I.; Corvalán, Alejandro H.; Armisén, Ricardo
    Gastric cancer (GC) is a complex and heterogeneous disease. In recent decades, The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) defined GC molecular subtypes. Unfortunately, these systems require high-cost and complex techniques and consequently their impact in the clinic has remained limited. Additionally, most of these studies are based on European, Asian, or North American GC cohorts. Herein, we report a molecular classification of Chilean GC patients into five subtypes, based on immunohistochemical (IHC) and in situ hybridization (ISH) methods. These were Epstein–Barr virus positive (EBV+), mismatch repair-deficient (MMR-D), epithelial to mesenchymal transition (EMT)-like, and accumulated (p53+) or undetected p53 (p53−). Given its lower costs this system has the potential for clinical applicability. Our results confirm relevant molecular alterations previously reported by TCGA and ACRG. We confirm EBV+ and MMR-D patients had the best prognosis and could be candidates for immunotherapy. Conversely, EMT-like displayed the poorest prognosis; our data suggest FGFR2 or KRAS could serve as potential actionable targets for these patients. Finally, we propose a low-cost step-by-step stratification system for GC patients. To the best of our knowledge, this is the first Latin American report on a molecular classification for GC. Pending further validation, this stratification system could be implemented into the routine clinic

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