Cerpa Leslie C, Sandoval Christopher, Escalante Paula, Cayún Juan P, Lavanderos María A, Alarcón-Concha Claudio, Kaempfe Guillermo, Moreno-Tapia Diego, Quiroz Camilo S, Gutierrez-Cáceres Carolina, Barajas Olga, Müller Bettina, Colombo Alicia, Donoso Gerardo, Nuñez Angie, Varela Nelson M, Quiñones Luis A
Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago, Chile.
Latin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF), Santiago, Chile.
Front Oncol. 2025 Jul 25;15:1589724. doi: 10.3389/fonc.2025.1589724. eCollection 2025.
Colorectal 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.
This study aimed to identify relevant genetic variants in , , , , , , , , , and genes, which, combined with clinical factors, could contribute to a predictive model for 5-FU-based chemotherapy safety in advanced colorectal cancer patients.
A 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.
Among the 16 variants analyzed in 82 patients, key findings included: The G allele of (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 (rs1801265) was linked to a higher neuropathy risk (OR = 4.58; p = 0.05). The deletion genotype (rs11280056) conferred protection against hematological adverse reactions (OR = 0.029; p = 0.001). On the other hand, the 3R genotype of 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.
This 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.
结直肠癌是智利第二大常见癌症，影响男女两性。约25%的病例为晚期诊断，五年生存率仅为14%。标准治疗包括手术切除，随后进行以5-氟尿嘧啶为基础的化疗，常联合奥沙利铂或伊立替康。然而，由于影响药物代谢的基因多态性，包括胸苷酸合成酶（TYMS）、二氢嘧啶脱氢酶（DPYD）、谷胱甘肽S-转移酶（GSTs）和DNA修复酶中的变异，患者反应差异很大。虽然已经研究了影响化疗结果的遗传因素，但其影响仍不明确，且因人群而异。尚未建立整合基因和临床变量以预测智利结直肠癌患者化疗安全性的模型。
本研究旨在鉴定在胸苷酸合成酶（TYMS）、二氢嘧啶脱氢酶（DPYD）、谷胱甘肽S-转移酶（GSTs）、甲基四氢叶酸还原酶（MTHFR）、多药耐药蛋白1（ABCB1）、多药耐药相关蛋白2（ABCC2）、拓扑异构酶1（TOP1）、错配修复蛋白（MLH1）、错配修复蛋白（MSH2）和错配修复蛋白（MSH6）基因中的相关基因变异，这些变异与临床因素相结合，有助于建立晚期结直肠癌患者基于5-氟尿嘧啶化疗安全性的预测模型。
对82例晚期结直肠癌患者进行回顾性巢式病例对照研究。分析16个基因变异，采用逻辑回归评估它们与不良反应及其严重程度的关联。建立多变量模型以预测化疗安全性。
在82例患者中分析的16个变异中，主要发现包括：胸苷酸合成酶（TYMS）（rs1695）的G等位基因对神经病变有保护作用（OR = 0.147；p = 0.012），但增加了粘膜炎风险（OR = 2.27；p = 0.036）。二氢嘧啶脱氢酶（DPYD）（rs1801265）的C等位基因与较高的神经病变风险相关（OR = 4.58；p = 0.05）。拓扑异构酶1（TOP1）缺失基因型（rs11280056）对血液学不良反应有保护作用（OR = 0.029；p = 0.001）。另一方面，胸苷酸合成酶（TYMS）5'非翻译区（rs45445694）的3R基因型是皮肤和皮下组织疾病的危险因素（OR = 6.40；p = 0.029）。建立了两个多变量模型以预测贫血（p = 0.027）和疼痛（p = 0.01）的发生。
本研究为开发基于药物遗传学的5-氟尿嘧啶相关不良反应预测模型奠定了基础，这些不良反应包括神经病变、粘膜炎以及血液学和皮肤毒性。未来的研究可能会完善这些模型，以实现个性化剂量调整，提高智利结直肠癌患者的化疗安全性。
