Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients.

Abstract

BACKGROUND:

Cancer patients carrying mutations in the dihydropyrimidine dehydrogenase gene (DPYD) have a high risk to experience severe drug-adverse effects following chemotherapy with fluoropyrimidine drugs such as 5-fluorouracil (5-FU) or capecitabine. The pretreatment detection of this impairment of pyrimidine catabolism could prevent serious, potentially lethal side effects. As known deleterious mutations explain only a limited proportion of the drug-adverse events, we systematically searched for additional DPYD variations associated with enhanced drug toxicity.

METHODOLOGY/PRINCIPAL FINDINGS:

We performed a whole gene approach covering the entire coding region and compared DPYD genotype frequencies between cancer patients with good (n = 89) and with poor (n = 39) tolerance of a fluoropyrimidine-based chemotherapy regimen. Applying logistic regression analysis and sliding window approaches we identified the strongest association with fluoropyrimidine-related grade III and IV toxicity for the non-synonymous polymorphism c.496A>G (p.Met166Val). We then confirmed our initial results using an independent sample of 53 individuals suffering from drug-adverse-effects. The combined odds ratio calculated for 92 toxicity cases was 4.42 [95% CI 2.12-9.23]; p (trend)<0.001; p (corrected) = 0.001; the attributable risk was 56.9%. Comparing tumor-type matched sets of samples, correlation of c.496A>G with toxicity was particularly present in patients with gastroesophageal and breast cancer, but did not reach significance in patients with colorectal malignancies.

CONCLUSION:

Our results show compelling evidence that, at least in distinct tumor types, a common DPYD polymorphism strongly contributes to the occurrence of fluoropyrimidine-related drug adverse effects. Carriers of this variant could benefit from individual dose adjustment of the fluoropyrimidine drug or alternate therapies.

• Authors: Eva Gross, Birgit Busse, Matthias Riemenschneider, Steffi Neubauer, Katharina Seck, Hanns-Georg Klein, Marion Kiechle, Florian Lordick, Alfons Meindl
• Journal: PloS one (PLoS One) Vol. 3 Issue 12 Pg. e4003 ( 2008) ISSN: 1932-6203 [Electronic] United States
• PMID: 19104657 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Dihydrouracil Dehydrogenase (NADP)
• Fluorouracil

Topics

• Aged
• Antimetabolites, Antineoplastic (administration & dosage, adverse effects, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Case-Control Studies
• Cohort Studies
• Dihydrouracil Dehydrogenase (NADP) (genetics)
• Drug-Related Side Effects and Adverse Reactions (genetics)
• Female
• Fluorouracil (administration & dosage, adverse effects, pharmacology)
• Gene Frequency
• Genetic Linkage
• Genetic Predisposition to Disease
• Humans
• Male
• Middle Aged
• Neoplasms (drug therapy, genetics)
• Polymorphism, Single Nucleotide (physiology)