Journal article
A new DPYD genotyping assay for improving the safety of 5-fluorouracil therapy.
- Sistonen J Institute of Clinical Chemistry, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland. johanna.sistonen@insel.ch
- Smith C
- Fu YK
- Largiadèr CR
- 2012-09-01
Published in:
- Clinica chimica acta; international journal of clinical chemistry. - 2012
Antineoplastic Combined Chemotherapy Protocols
Dihydrouracil Dehydrogenase (NADP)
Fluorouracil
Genotype
Genotyping Techniques
Humans
Safety
English
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® 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 (~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.
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® 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 (~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.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1016/j.cca.2012.08.015
- PMID 22935545
- Persistent URL
- https://sonar.ch/global/documents/1431
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