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Pharmacogenomics in colorectal cancer: a genome-wide association study to predict toxicity after 5-fluorouracil or FOLFOX administration

The Pharmacogenomics Journal volume 13, pages 209–217 (2013)Cite this article

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Abstract

The development of genotyping technologies has allowed for wider screening for inherited causes of variable outcomes following drug administration. We have performed a genome-wide association study (GWAS) on 221 colorectal cancer (CRC) patients that had been treated with 5-fluorouracil (5-FU), either alone or in combination with oxaliplatin (FOLFOX). A validation set of 791 patients was also studied. Seven SNPs (rs16857540, rs2465403, rs10876844, rs10784749, rs17626122, rs7325568 and rs4243761) showed evidence of association (pooled P-values 0.020, 9.426E-03, 0.010, 0.017, 0.042, 2.302E-04, 2.803E-03) with adverse drug reactions (ADRs). This is the first study to explore the genetic basis of inter-individual variation in toxicity responses to the administration of 5-FU or FOLFOX in CRC patients on a genome-wide scale.

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Acknowledgements

We are sincerely grateful to all patients participating in this study, who were recruited as part of the EPICOLON project. This work was supported by Grants from Fondo de Investigación Sanitatia/FEDER (06/1384, CP06/0267, 06/1712, 08/0024, 08/1276, PI08-1359, PI08-1635, PS09/02368), Instituto de Salud Carlos III (Acción Transversal de Cáncer), Xunta de Galicia (PGIDT08CSA005208PR, PGIDIT07PXIB9101209PR), Ministerio de Ciencia e Innovación SAF 07-64873 and SAF 2010-19273), Fundación Privada Olga Torres (CRP), Fundación Barrie de la Maza (Programa DIANA), Asociación Española contra el Cáncer (Fundación Científica y Junta de Barcelona), Fundación Mutua Madrileña (LFLA), Fundación Ramón Areces (LFLA), Grant 209/12/2009 Agencia d'Informació Avaluació i Qualitat en Salut, and FP7 CHIBCHA Consortium (SCB and ACar). CIBERehd and CIBERER are funded by the Instituto de Salud Carlos III. SCB and CFR are supported by contracts from the Fondo de Investigación Sanitaria (CP 03-0070 to SCB and PS09/02368 to CFR). JBCs work was supported by the Wellcome Trust core award Grant number 075491/Z/04. We acknowledge the Wellcome Trust Case Control Consortium for making available data about SNP tagging of common CNVs (http://www.wtccc.org.uk/wtcccplus_cnv/supplemental.shtml).'

Author information

Author notes

  1. C Fernandez-Rozadilla, J B Cazier, V Moreno, M Crous-Bou, E Guinó, G Durán, M J Lamas, R López, S Candamio, E Gallardo, L Paré, M Baiget, D Páez, L A López-Fernández, L Cortejoso, M I García, L Bujanda, D González, V Gonzalo, L Rodrigo, J M Reñé, R Jover, A Brea-Fernández, M Andreu, X Bessa, X Llor, R Xicola, C Palles, I Tomlinson, S Castellví-Bel, A Castells, C Ruiz-Ponte and A Carracedo: C Ruiz-Ponte and A Carracedo: These authors contributed equally to this work.

  2. For the Gastrointestinal Oncology Group of the Spanish Gastroenterological Association. All authors are listed in a Supplementary note.

Authors and Affiliations

  1. Galician Public Foundation of Genomic Medicine (FPGMX)-Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)-Genomics Medicine Group-Hospital Clínico Santiago de Compostela-University of Santiago de Compostela, Santiago de Compostela, Spain

    C Fernandez-Rozadilla, A Brea-Fernández, C Ruiz-Ponte & A Carracedo

  2. Nuffield Department of Medicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    J B Cazier, C Palles & I Tomlinson

  3. Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Centre (IDIBELL), CIBERESP, Barcelona, Spain

    V Moreno, M Crous-Bou & E Guinó

  4. Faculty of Medicine, University of Barcelona, Barcelona, Spain

    V Moreno

  5. Oncology Pharmacy Unit, Complexo Hospitalario Universitario of Santiago (CHUS), Santiago de Compostela, Spain

    G Durán & M J Lamas

  6. Clinical Oncology Department, Complexo Hospitalario Universitario of Santiago (CHUS), Santiago de Compostela, Spain

    R López, S Candamio & E Gallardo

  7. Molecular Genetics Unit, Hospital de Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

    L Paré & M Baiget

  8. Medic Oncology Department, Hospital de Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

    D Páez

  9. Pharmacogenetics & Pharmacogenomics Laboratory, Servicio de Farmacia, Hospital General Universitario Gregorio Marañón, Madrid, Spain

    L A López-Fernández, L Cortejoso & M I García

  10. Gastroenterology Department, Donostia Hospital, CIBERehd, University of the Basque Country, San Sebastián, Spain

    L Bujanda

  11. Gastroenterology Department, Hospital de Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

    D González

  12. Department of Gastroenterology, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain

    V Gonzalo, S Castellví-Bel & A Castells

  13. Gastroenterology Department, Hospital Universitario Central de Asturias, Oviedo, Spain

    L Rodrigo

  14. Gastroenterology Department, Hospital Universitari Arnau de Vilanova, Lleida, IRBLleida, Universitat de Lleida, Lleida, Spain

    J M Reñé

  15. Gastroenterology Department, Hospital General de Alicante, Alicante, Spain

    R Jover

  16. Gastroenterology Department, Hospital del Mar, Barcelona, Spain

    M Andreu & X Bessa

  17. Section of Digestive Diseases and Nutrition, University of Illinois at Chicago, Chicago, IL, USA

    X Llor & R Xicola

  18. NIHR Comprehensive Biomedical Research Centre, University of Oxford, Oxford, UK

    I Tomlinson

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  1. C Fernandez-Rozadilla
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  33. A Carracedo
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Correspondence to A Carracedo.

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Fernandez-Rozadilla, C., Cazier, J., Moreno, V. et al. Pharmacogenomics in colorectal cancer: a genome-wide association study to predict toxicity after 5-fluorouracil or FOLFOX administration. Pharmacogenomics J 13, 209–217 (2013). https://doi.org/10.1038/tpj.2012.2

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