Contribution of dihydropyrimidinase gene alterations to the development of serious toxicity in fluoropyrimidine-treated cancer patients.

Abstract

PURPOSE:

Decreased 5-fluorouracil catabolism has been considered a major factor contributing to fluoropyrimidine (FP)-related toxicity. Alterations in the dihydropyrimidine dehydrogenase gene coding for the first and rate-limiting enzyme of FP catabolic pathway could explain toxicity in only a limited proportion of FP-treated patients. The importance of gene variants in dihydropyrimidinase (DPYS) coding for subsequent catabolic enzyme of FP degradation is not fully understood.

METHODS:

We performed genotyping of DPYS based on denaturing high-performance liquid chromatography in 113 cancer patients including 67 with severe FP-related toxicity and 46 without toxicity excellently tolerating FPs treatment.

RESULTS:

We detected nine DPYS variants including four located in non-coding sequence (c.-1T>C, IVS1+34C>G, IVS1-58T>C, and novel IVS4+11G>T), four silent (c.15G>A, c.216C>T, and novel c.105C>T and c.324C>A), and one novel missense variant c.1441C>T (p.R481W). All novel alterations were detected once only in patients without toxicity. The c.-1T>C and IVS1-58T>C variants were found to modify the risk of toxicity. The CC carriers of the c.-1C alleles were at higher risk of mucositis (OR = 4.13; 95% CI = 1.51-11.31; P = 0.006) and gastrointestinal toxicity (OR = 3.54; 95% CI = 1.59-7.88; P = 0.002), whereas the presence of the IVS1-58C allele decreased the risk of gastrointestinal toxicity (OR = 0.4; 95% CI = 0.17-0.93; P = 0.03) and leucopenia (OR = 0.29; 95% CI = 0.08-1.01; P = 0.05).

CONCLUSIONS:

Our results indicate that missense and nonsense variants in DPYS are infrequent, however, the development of serious primarily gastrointestinal toxicity could be influenced by non-coding DPYS sequence variants c.-1T>C and IVS1-58T>C.

• Authors: Julie Fidlerova, Petra Kleiblova, Matej Bilek, Stanislav Kormunda, Zuzana Formankova, Jan Novotny, Zdenek Kleibl
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 65 Issue 4 Pg. 661-9 (Mar 2010) ISSN: 1432-0843 [Electronic] Germany
• PMID: 19649633 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Amidohydrolases
• dihydropyrimidinase
• Fluorouracil

Topics

• Adult
• Aged
• Alleles
• Amidohydrolases (genetics, metabolism)
• Antimetabolites, Antineoplastic (adverse effects, metabolism)
• Base Sequence
• Chi-Square Distribution
• DNA Mutational Analysis
• Drug-Related Side Effects and Adverse Reactions (chemically induced, genetics)
• Female
• Fluorouracil (adverse effects, metabolism)
• Gene Frequency
• Genotype
• Haplotypes
• Humans
• Male
• Middle Aged
• Mutation
• Neoplasms (drug therapy, genetics)
• Odds Ratio