4.7 Article

A new DPYD genotyping assay for improving the safety of 5-fluorouracil therapy

期刊

CLINICA CHIMICA ACTA
卷 414, 期 -, 页码 109-111

出版社

ELSEVIER SCIENCE BV
DOI: 10.1016/j.cca.2012.08.015

关键词

5-Fluorouracil; DPYD; Genotyping; Microarray; Pharmacogenomics

资金

  1. Swiss National Science Foundation [31003A_138285]
  2. 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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