Novel approaches for the discovery of pharmacogenetic biomarkers of chemotoxicity in patients with colorectal cancer
Por:
Simoes, AR, González, SC, Lopez-Doldan, MD, Duran, G, Fernández-Montes, A, Fernandez, MP, Fernandez, MS, Mata, JG, Paez, D, Riera, P, Guino, E, Lopez-Fernandez, L, de Santiago, BG, Aspiroz, EL, Rojas, A, Castells, A, Castellvi-Bel, S, Ponte, CR, Vymetalkova, V, Carracedo, A, Fernandez-Rozadilla, C
Publicada:
1 nov 2025
Ahead of Print:
1 jul 2025
Resumen:
Background and Purpose Chemotherapeutic treatment for colorectal cancer (colorectal cancer) allows for increased patient overall survival. However, current therapeutic regimens are often associated with the development of adverse drug reactions, which represent a morbidity, mortality and economic issue. We propose to identify novel germline markers that allow us to predict adverse drug reactions development after colorectal cancer chemotherapy. Experimental Approach For that purpose, we selected 163 colorectal cancer patients with severe adverse drug reactions (CTCAE grades 3-4) and 52 controls and applied whole-exome sequencing (WES) to discover novel germline toxicity variants. Key Results We found 13 cases carrying actionable dihydropyrimidine dehydrogenase gene (DPYD) variants and a novel, potentially pathogenic DPYD variant - c.2071G > T, p.(V691L), rs202212118. Moreover, we found 30 novel rare, high-impact variants in 14 reported genes. We also identified seven patients carrying more than one variant in the same gene or pathway, with one patient hinting at a potential digenic inheritance. Using an exome-wide approach, we discovered and independently validated three novel candidate toxicity genes (ALDH9A1, FAM83A and EPX). Gene-based analyses also provided 14 genes significantly associated with neuropathy, skin toxicity and cardiotoxicity. Conclusions and Implications Overall, the present work has utilised state-of-the-art approaches to uncover several novel candidate toxicity variants/genes.
Filiaciones:
Simoes, AR:
Inst Invest Sanitaria Santiago IDIS, Santiago De Compostela, Spain
González, SC:
Inst Invest Sanitaria Santiago IDIS, Santiago De Compostela, Spain
Lopez-Doldan, MD:
Complexo Hosp Univ Ourense, Oncol Pharm Unit, Orense, Spain
Duran, G:
Univ Hosp Santiago De Compostela Pharm Serv, Pharm Dept, Santiago De Compostela, Spain
Fernández-Montes, A:
Complexo Hosp Univ Ourense, Med Oncol Unit, Orense, Spain
Fernandez, MP:
Complexo Hosp Univ Ourense, Oncol Pharm Unit, Orense, Spain
Fernandez, MS:
Complexo Hosp Univ Ourense, Med Oncol Unit, Orense, Spain
Mata, JG:
Complexo Hosp Univ Ourense, Med Oncol Unit, Orense, Spain
Paez, D:
Hosp Santa Creu & Sant Pau, Med Oncol Dept, Barcelona, Spain
Inst Invest Biomed St Pau, Translat Med Oncol Lab, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Pharm Dept, Barcelona, Spain
Inst Salud Carlos III, Ctr Biomed Res Network Rare Dis CIBERER, Madrid, Spain
Riera, P:
Inst Invest Biomed St Pau, Translat Med Oncol Lab, Barcelona, Spain
Guino, E:
Catalan Inst Oncol, Oncol Data Analyt Program, Barcelona, Spain
Colorectal Canc Grp, Bellvitge Inst Biomed Res, Barcelona, Spain
Mol Mech & Expt Therapy Oncol ONCOBELL Program, Barcelona, Spain
Inst Salud Carlos III, Biomed Res Ctr Network Epidemiol & Publ Hlth, Consortium CIBERESP, Madrid, Spain
Lopez-Fernandez, L:
Hosp Gen Univ Gregorio Maranon, Serv Farm, Madrid, Spain
Inst Invest Sanitaria Gregorio Maranon, Madrid, Spain
de Santiago, BG:
Infanta Sofia Univ Hosp, Pharm Serv, Madrid, Spain
Aspiroz, EL:
Infanta Sofia Univ Hosp, Pharm Serv, Madrid, Spain
Univ Europea Madrid, Fac Med Hlth & Sports, Madrid, Spain
Rojas, A:
Tecnol Monterrey, Sch Med & Hlth Sci, Monterrey, Mexico
Castells, A:
Hosp Clin Barcelona, Gastroenterol Unit, Barcelona, Spain
Inst Invest Biomed August Pi i Sunyer IDIBAPS, Gastroenterol Dept, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Castellvi-Bel, S:
Hosp Clin Barcelona, Gastroenterol Unit, Barcelona, Spain
Inst Invest Biomed August Pi i Sunyer IDIBAPS, Gastroenterol Dept, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Hosp Clin Barcelona, Gastroenterol Dept, Barcelona, Spain
Ponte, CR:
Inst Invest Sanitaria Santiago IDIS, Santiago De Compostela, Spain
Galician Publ Fdn Genom Med FPGMX, Santiago De Compostela, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain
Vymetalkova, V:
Charles Univ Prague, Czech Acad Sci, Inst Expt Med, Dept Mol Biol Canc, Prague, Czech Republic
Carracedo, A:
Inst Invest Sanitaria Santiago IDIS, Santiago De Compostela, Spain
Galician Publ Fdn Genom Med FPGMX, Santiago De Compostela, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain
Univ Santiago De Compostela, Genom Med Grp, Santiago De Compostela, Spain
Fernandez-Rozadilla, C:
Inst Invest Sanitaria Santiago IDIS, Santiago De Compostela, Spain
Galician Publ Fdn Genom Med FPGMX, Santiago De Compostela, Spain
Univ Santiago De Compostela, Genom Med Grp, Santiago De Compostela, Spain
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