Use of Exome Sequencing to Determine the Full Profile of Genetic Variants in the Fluoropyrimidine Pathway in Colorectal Cancer Patients Affected by Severe Toxicity

Abstract

Aim: To identify genetic variants associated with capecitabine toxicity in fluoropyrimidine pathway genes using exome sequencing. Patients & methods: Exomes from eight capecitabine-treated patients with severe adverse reactions (grade >2), among a population of 319, were sequenced (Ion Proton). SNPs in genes classified as potentially damaging (Sorting Intolerant from Tolerant and Polymorphism Phenotyping v2) were tested for association with toxicity in a validation cohort of 319 capecitabine-treated patients. Results: A total of 17 nonsynonymous genetic variants were identified. Of these, five putative damaging SNPs in DPYD, ABCC4 and MTHFR were genotyped in the validation cohort. DPYD rs1801160 was associated with the risk of toxicity (p = 0.029) and MTHFR rs1801133 with delayed administration of chemotherapy due to toxicity (p = 0.047). Conclusion: Exome sequencing revealed two specific biomarkers of the risk of toxicity to capecitabine.

Keywords::

• adverse drug reaction
• capecitabine
• next-generation sequencing

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/full/10.2217/pgs-2017-0118

Financial & competing interests disclosure

This study was partially supported by the Ministry of Economy and Competitiveness ISCIII-FIS grants PI12/00056, CPII13/00008 and PEJ16/MED/AI-1260 (LA López-Fernández) and grant PTA2013–8539-I (MI García), by Consejería de Educación y Deporte de la Comunidad de Madrid PEJ15/BIO/TL-0603 (C Blanco), and by Gregorio Marañón Health Research Institute (X García-González). The study was co-funded by ERDF Funds (FEDER) from the European Commission, ‘A way of making Europe’. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate Institutional Review Board approval and have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, informed consent has been obtained from the participants involved.

Additional information

Funding

This study was partially supported by the Ministry of Economy and Competitiveness ISCIII-FIS grants PI12/00056, CPII13/00008 and PEJ16/MED/AI-1260 (LA López-Fernández) and grant PTA2013–8539-I (MI García), by Consejería de Educación y Deporte de la Comunidad de Madrid PEJ15/BIO/TL-0603 (C Blanco), and by Gregorio Marañón Health Research Institute (X García-González). The study was co-funded by ERDF Funds (FEDER) from the European Commission, ‘A way of making Europe’. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.