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Variants in the dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase and thymidylate synthase genes predict early toxicity of 5-fluorouracil in colorectal cancer patients.
J Int Med Res 2010 May-Jun; 38(3):870-83JI

Abstract

Adverse drug reactions to 5-fluorouracil (5-FU)-based chemotherapy have been reported to be due, in part, to genetic variants of the genes for the drug-related enzymes thymidylate synthase (TS; TYMS gene), methylenetetrahydrofolate reductase (MTHFR gene) and dihydropyrimidine dehydrogenase (DPD; DPYD gene). This study investigated whether selected genetic variants of the TYMS, MTHFR and DPYD genes predict 5-FU-related early toxicity. The prevalence of the genetic variants was determined in 122 colorectal cancer patients and in a reference population of 320 blood donors. Subgroup analysis of 68 of the colorectal cancer patients was carried out to determine the relationship between selected gene variants detected in peripheral mono nuclear cells and tolerability during the first or second cycle of 5-FU based treatment. Toxicity was linked to the TYMS 2R/2R variant (relative risk [RR] 1.66; sensitivity 0.37; specificity 0.77) and to the MTHFR c1298 C/C genetic variant (RR 1.77; sensitivity 0.17; specificity 0.91). Patients with the genetic variant IVS14+1 G/A or c1896 C/T in the DPYD gene had a statistically significant increased risk of experiencing toxicity (RR 2 and 6, respectively), both having a high specificity (0.97 and 0.98, respectively) and low sensitivity (0.04 and 0.13, respectively). It is concluded that pre-treatment detection of genetic variants can help to predict early toxicity experienced by patients receiving 5-FU-based chemotherapy.

Authors+Show Affiliations

Department of Clinical Pathology, Hospital South, Naestved, Denmark. mick@regionsjaelland.dkNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

20819423

Citation

Kristensen, M H., et al. "Variants in the Dihydropyrimidine Dehydrogenase, Methylenetetrahydrofolate Reductase and Thymidylate Synthase Genes Predict Early Toxicity of 5-fluorouracil in Colorectal Cancer Patients." The Journal of International Medical Research, vol. 38, no. 3, 2010, pp. 870-83.
Kristensen MH, Pedersen PL, Melsen GV, et al. Variants in the dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase and thymidylate synthase genes predict early toxicity of 5-fluorouracil in colorectal cancer patients. J Int Med Res. 2010;38(3):870-83.
Kristensen, M. H., Pedersen, P. L., Melsen, G. V., Ellehauge, J., & Mejer, J. (2010). Variants in the dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase and thymidylate synthase genes predict early toxicity of 5-fluorouracil in colorectal cancer patients. The Journal of International Medical Research, 38(3), pp. 870-83.
Kristensen MH, et al. Variants in the Dihydropyrimidine Dehydrogenase, Methylenetetrahydrofolate Reductase and Thymidylate Synthase Genes Predict Early Toxicity of 5-fluorouracil in Colorectal Cancer Patients. J Int Med Res. 2010;38(3):870-83. PubMed PMID: 20819423.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Variants in the dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase and thymidylate synthase genes predict early toxicity of 5-fluorouracil in colorectal cancer patients. AU - Kristensen,M H, AU - Pedersen,P L, AU - Melsen,G V, AU - Ellehauge,J, AU - Mejer,J, PY - 2010/9/8/entrez PY - 2010/9/8/pubmed PY - 2010/9/30/medline SP - 870 EP - 83 JF - The Journal of international medical research JO - J. Int. Med. Res. VL - 38 IS - 3 N2 - Adverse drug reactions to 5-fluorouracil (5-FU)-based chemotherapy have been reported to be due, in part, to genetic variants of the genes for the drug-related enzymes thymidylate synthase (TS; TYMS gene), methylenetetrahydrofolate reductase (MTHFR gene) and dihydropyrimidine dehydrogenase (DPD; DPYD gene). This study investigated whether selected genetic variants of the TYMS, MTHFR and DPYD genes predict 5-FU-related early toxicity. The prevalence of the genetic variants was determined in 122 colorectal cancer patients and in a reference population of 320 blood donors. Subgroup analysis of 68 of the colorectal cancer patients was carried out to determine the relationship between selected gene variants detected in peripheral mono nuclear cells and tolerability during the first or second cycle of 5-FU based treatment. Toxicity was linked to the TYMS 2R/2R variant (relative risk [RR] 1.66; sensitivity 0.37; specificity 0.77) and to the MTHFR c1298 C/C genetic variant (RR 1.77; sensitivity 0.17; specificity 0.91). Patients with the genetic variant IVS14+1 G/A or c1896 C/T in the DPYD gene had a statistically significant increased risk of experiencing toxicity (RR 2 and 6, respectively), both having a high specificity (0.97 and 0.98, respectively) and low sensitivity (0.04 and 0.13, respectively). It is concluded that pre-treatment detection of genetic variants can help to predict early toxicity experienced by patients receiving 5-FU-based chemotherapy. SN - 0300-0605 UR - https://www.unboundmedicine.com/medline/citation/20819423/Variants_in_the_dihydropyrimidine_dehydrogenase_methylenetetrahydrofolate_reductase_and_thymidylate_synthase_genes_predict_early_toxicity_of_5_fluorouracil_in_colorectal_cancer_patients_ L2 - http://journals.sagepub.com/doi/full/10.1177/147323001003800313?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -