Novel approaches for the discovery of pharmacogenetic biomarkers of chemotoxicity in patients with colorectal cancer
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 is...
| Autores: | , , , , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
| Repositorio: | r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
| OAI Identifier: | oai:iibsantpau.fundanetsuite.com:p20302 |
| Acceso en línea: | https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=20302 |
| Access Level: | acceso abierto |
| Palabra clave: | adverse drug reactions colorectal cancer personalised medicine pharmacogenomics |
| Sumario: | 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. |
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