Journal
CLINICA CHIMICA ACTA
Volume 414, Issue -, Pages 109-111Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.cca.2012.08.015
Keywords
5-Fluorouracil; DPYD; Genotyping; Microarray; Pharmacogenomics
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Funding
- Swiss National Science Foundation [31003A_138285]
- Swiss National Science Foundation (SNF) [31003A_138285] Funding Source: Swiss National Science Foundation (SNF)
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Background: Chemotherapeutic use of 5-fluorouracil (5FU) is compromised by 10-20% of patients developing severe toxicity. Recently described genetic variation in dihydropyrimidine dehydrogenase (DPYD) has been shown to be a major predictor of 5FU toxicity. Here, we describe a new genotyping assay for routine clinical use that covers all the major DPYD risk variants. Methods: Genomic regions targeting DPYD risk variants (c.1129-5923C>G, c.1679T>G/A, c.1905+1G>A, c.2846A>T) and additional markers (c.234-123G>C, c.496A>G, c.775A>G) were amplified in a multiplex PCR reaction. The subsequent steps including allele-specific primer extension, hybridization of the primers to a microarray, scanning of the array, and data analysis were automated within the INFINITI (R) Analyzer (AutoGenomics). The assay was validated by analyzing 107 blood samples obtained from patients previously re-sequenced for the DPYD. Results: The genotypes obtained with the developed assay were 100% concordant with the re-sequencing. The procedure is suitable for routine clinical use since the results are obtained within one day. For heterozygous risk variant carriers (similar to 7% of Europeans), the treatment can be adjusted by 5FU dose reduction, whereas carriers of two risk alleles should be treated with an alternative therapy. Conclusions: The developed assay provides a novel tool to improve the safety of commonly used 5FU-based chemotherapies. (C) 2012 Elsevier B.V. All rights reserved.
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