Genetic variants and clinical determinants affecting the response to 5-Fluorouracil-based treatment in Chilean patients with advanced colorectal cancer
BackgroundColorectal cancer is the second most prevalent cancer in Chile, affecting both sexes. Late-stage diagnosis occurs in approximately 25% of cases, with a five-year survival rate of only 14%. Standard treatment involves surgical resection followed by 5-fluorouracil-based chemotherapy, often c...
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Frontiers Media S.A.
2025-07-01
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| author | Leslie C. Cerpa Leslie C. Cerpa Leslie C. Cerpa Christopher Sandoval Paula Escalante Juan P. Cayún Juan P. Cayún María A. Lavanderos María A. Lavanderos María A. Lavanderos Claudio Alarcón-Concha Claudio Alarcón-Concha Guillermo Kaempfe Diego Moreno-Tapia Camilo S. Quiroz Carolina Gutierrez-Cáceres Carolina Gutierrez-Cáceres Olga Barajas Olga Barajas Bettina Müller Bettina Müller Alicia Colombo Alicia Colombo Gerardo Donoso Gerardo Donoso Angie Nuñez Nelson M. Varela Nelson M. Varela Luis A. Quiñones Luis A. Quiñones Luis A. Quiñones |
| author_facet | Leslie C. Cerpa Leslie C. Cerpa Leslie C. Cerpa Christopher Sandoval Paula Escalante Juan P. Cayún Juan P. Cayún María A. Lavanderos María A. Lavanderos María A. Lavanderos Claudio Alarcón-Concha Claudio Alarcón-Concha Guillermo Kaempfe Diego Moreno-Tapia Camilo S. Quiroz Carolina Gutierrez-Cáceres Carolina Gutierrez-Cáceres Olga Barajas Olga Barajas Bettina Müller Bettina Müller Alicia Colombo Alicia Colombo Gerardo Donoso Gerardo Donoso Angie Nuñez Nelson M. Varela Nelson M. Varela Luis A. Quiñones Luis A. Quiñones Luis A. Quiñones |
| author_sort | Leslie C. Cerpa |
| collection | DOAJ |
| description | BackgroundColorectal cancer is the second most prevalent cancer in Chile, affecting both sexes. Late-stage diagnosis occurs in approximately 25% of cases, with a five-year survival rate of only 14%. Standard treatment involves surgical resection followed by 5-fluorouracil-based chemotherapy, often combined with oxaliplatin or irinotecan. However, patient responses vary significantly due to genetic polymorphisms affecting drug metabolism, including variants in TYMS, DPYD, GSTs, and DNA repair enzymes. While genetic factors influencing chemotherapy outcomes have been studied, their impact remains unclear and varies across populations. No predictive model integrating genetic and clinical variables for chemotherapy safety in Chilean colorectal cancer patients has been established.ObjectiveThis study aimed to identify relevant genetic variants in TYMS, TYMP, DPYD, GSTP1, MTHFR, ERCC2, ABCB1, ABCC2, ABCC4, and ABCG2 genes, which, combined with clinical factors, could contribute to a predictive model for 5-FU-based chemotherapy safety in advanced colorectal cancer patients.MethodsA retrospective nested case-control study was conducted on 82 advanced colorectal cancer patients. Sixteen genetic variants were analyzed to assess their association with adverse reactions and their severity using logistic regression. Multivariate models were developed to predict chemotherapy safety.ResultsAmong the 16 variants analyzed in 82 patients, key findings included: The G allele of GSTP1 (rs1695) was protective against neuropathy (OR = 0.147; p = 0.012) but increased mucositis risk (OR = 2.27; p = 0.036). The C allele of DPYD (rs1801265) was linked to a higher neuropathy risk (OR = 4.58; p = 0.05). The TYMS deletion genotype (rs11280056) conferred protection against hematological adverse reactions (OR = 0.029; p = 0.001). On the other hand, the 3R genotype of TYMS 5’UTR (rs45445694) is associated as a risk factor for skin and subcutaneous tissue disorders (OR = 6.40; p = 0.029). Two multivariate models were developed to predict anemia (p = 0.027) and pain (p = 0.01) development.ConclusionsThis study provides a foundation for developing pharmacogenetic-based predictive models for adverse reactions associated with 5-FU, including neuropathy, mucositis, and hematological and skin toxicities. Future research may refine these models to enable personalized dose adjustments, improving chemotherapy safety in Chilean colorectal patients. |
| format | Article |
| id | doaj-art-e8a487f0f74b471f87116ffd25fbbcb6 |
| institution | Matheson Library |
| issn | 2234-943X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Oncology |
| spelling | doaj-art-e8a487f0f74b471f87116ffd25fbbcb62025-07-25T04:10:23ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2025-07-011510.3389/fonc.2025.15897241589724Genetic variants and clinical determinants affecting the response to 5-Fluorouracil-based treatment in Chilean patients with advanced colorectal cancerLeslie C. Cerpa0Leslie C. Cerpa1Leslie C. Cerpa2Christopher Sandoval3Paula Escalante4Juan P. Cayún5Juan P. Cayún6María A. Lavanderos7María A. Lavanderos8María A. Lavanderos9Claudio Alarcón-Concha10Claudio Alarcón-Concha11Guillermo Kaempfe12Diego Moreno-Tapia13Camilo S. Quiroz14Carolina Gutierrez-Cáceres15Carolina Gutierrez-Cáceres16Olga Barajas17Olga Barajas18Bettina Müller19Bettina Müller20Alicia Colombo21Alicia Colombo22Gerardo Donoso23Gerardo Donoso24Angie Nuñez25Nelson M. Varela26Nelson M. Varela27Luis A. Quiñones28Luis A. Quiñones29Luis A. Quiñones30Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago, ChileLatin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF), Santiago, ChileCenter for Cancer Prevention and Control (CECAN), Santiago, ChileClinical Laboratory, Felix Bulnes Clinical Hospital, Santiago, ChileLaboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago, ChileLaboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago, ChileLatin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF), Santiago, ChileLaboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago, ChileLatin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF), Santiago, ChileDepartment of Basic Sciences, Faculty of Sciences, University of Bío, Bío, ChileLaboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago, ChileEscuela de Medicina, Fundación Instituto Profesional Duoc UC, Santiago, ChileLaboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago, ChileLaboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago, ChileLaboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago, ChileLaboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago, ChileDepartment of Pharmaceutical Sciences and Technology, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, ChileCenter for Cancer Prevention and Control (CECAN), Santiago, ChileClinical Hospital of University of Chile, Santiago, ChileCenter for Cancer Prevention and Control (CECAN), Santiago, ChileNational Cancer Institute, Santiago, ChileCenter for Cancer Prevention and Control (CECAN), Santiago, Chile0Biobank of Fluids and Tissues of the University of Chile, Santiago, ChileCenter for Cancer Prevention and Control (CECAN), Santiago, Chile0Biobank of Fluids and Tissues of the University of Chile, Santiago, Chile1Faculty of Pharmacy, University of Costa Rica, San Jose, Costa RicaLaboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago, ChileLatin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF), Santiago, ChileLaboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago, ChileLatin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF), Santiago, ChileDepartment of Pharmaceutical Sciences and Technology, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, ChileBackgroundColorectal cancer is the second most prevalent cancer in Chile, affecting both sexes. Late-stage diagnosis occurs in approximately 25% of cases, with a five-year survival rate of only 14%. Standard treatment involves surgical resection followed by 5-fluorouracil-based chemotherapy, often combined with oxaliplatin or irinotecan. However, patient responses vary significantly due to genetic polymorphisms affecting drug metabolism, including variants in TYMS, DPYD, GSTs, and DNA repair enzymes. While genetic factors influencing chemotherapy outcomes have been studied, their impact remains unclear and varies across populations. No predictive model integrating genetic and clinical variables for chemotherapy safety in Chilean colorectal cancer patients has been established.ObjectiveThis study aimed to identify relevant genetic variants in TYMS, TYMP, DPYD, GSTP1, MTHFR, ERCC2, ABCB1, ABCC2, ABCC4, and ABCG2 genes, which, combined with clinical factors, could contribute to a predictive model for 5-FU-based chemotherapy safety in advanced colorectal cancer patients.MethodsA retrospective nested case-control study was conducted on 82 advanced colorectal cancer patients. Sixteen genetic variants were analyzed to assess their association with adverse reactions and their severity using logistic regression. Multivariate models were developed to predict chemotherapy safety.ResultsAmong the 16 variants analyzed in 82 patients, key findings included: The G allele of GSTP1 (rs1695) was protective against neuropathy (OR = 0.147; p = 0.012) but increased mucositis risk (OR = 2.27; p = 0.036). The C allele of DPYD (rs1801265) was linked to a higher neuropathy risk (OR = 4.58; p = 0.05). The TYMS deletion genotype (rs11280056) conferred protection against hematological adverse reactions (OR = 0.029; p = 0.001). On the other hand, the 3R genotype of TYMS 5’UTR (rs45445694) is associated as a risk factor for skin and subcutaneous tissue disorders (OR = 6.40; p = 0.029). Two multivariate models were developed to predict anemia (p = 0.027) and pain (p = 0.01) development.ConclusionsThis study provides a foundation for developing pharmacogenetic-based predictive models for adverse reactions associated with 5-FU, including neuropathy, mucositis, and hematological and skin toxicities. Future research may refine these models to enable personalized dose adjustments, improving chemotherapy safety in Chilean colorectal patients.https://www.frontiersin.org/articles/10.3389/fonc.2025.1589724/fullcolorectal cancer5-FUpharmacogeneticspharmacogenomicsadverse drug reactions |
| spellingShingle | Leslie C. Cerpa Leslie C. Cerpa Leslie C. Cerpa Christopher Sandoval Paula Escalante Juan P. Cayún Juan P. Cayún María A. Lavanderos María A. Lavanderos María A. Lavanderos Claudio Alarcón-Concha Claudio Alarcón-Concha Guillermo Kaempfe Diego Moreno-Tapia Camilo S. Quiroz Carolina Gutierrez-Cáceres Carolina Gutierrez-Cáceres Olga Barajas Olga Barajas Bettina Müller Bettina Müller Alicia Colombo Alicia Colombo Gerardo Donoso Gerardo Donoso Angie Nuñez Nelson M. Varela Nelson M. Varela Luis A. Quiñones Luis A. Quiñones Luis A. Quiñones Genetic variants and clinical determinants affecting the response to 5-Fluorouracil-based treatment in Chilean patients with advanced colorectal cancer Frontiers in Oncology colorectal cancer 5-FU pharmacogenetics pharmacogenomics adverse drug reactions |
| title | Genetic variants and clinical determinants affecting the response to 5-Fluorouracil-based treatment in Chilean patients with advanced colorectal cancer |
| title_full | Genetic variants and clinical determinants affecting the response to 5-Fluorouracil-based treatment in Chilean patients with advanced colorectal cancer |
| title_fullStr | Genetic variants and clinical determinants affecting the response to 5-Fluorouracil-based treatment in Chilean patients with advanced colorectal cancer |
| title_full_unstemmed | Genetic variants and clinical determinants affecting the response to 5-Fluorouracil-based treatment in Chilean patients with advanced colorectal cancer |
| title_short | Genetic variants and clinical determinants affecting the response to 5-Fluorouracil-based treatment in Chilean patients with advanced colorectal cancer |
| title_sort | genetic variants and clinical determinants affecting the response to 5 fluorouracil based treatment in chilean patients with advanced colorectal cancer |
| topic | colorectal cancer 5-FU pharmacogenetics pharmacogenomics adverse drug reactions |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2025.1589724/full |
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