Journal article
Comparative Functional Analysis of DPYD Variants of Potential Clinical Relevance to Dihydropyrimidine Dehydrogenase Activity
Cancer research (Chicago, Ill.), Vol.74(9), pp.2545-2554
05/01/2014
DOI: 10.1158/0008-5472.CAN-13-2482
PMCID: PMC4012613
PMID: 24648345
Abstract
Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of the uracil catabolic pathway, being critically important for inactivation of the commonly prescribed anti-cancer drug 5-fluorouracil (5-FU). DPD impairment leads to increased exposure to 5-FU and, in turn, increased anabolism of 5-FU to cytotoxic nucleotides, resulting in more severe clinical adverse effects. Numerous variants within the gene coding for DPD, DPYD, have been described, although only a few have been demonstrated to reduce DPD enzyme activity. To identify DPYD variants that alter enzyme function, we expressed 80 protein-coding variants in an isogenic mammalian system and measured their capacities to convert 5-FU to dihydro-fluorouracil, the product of DPD catabolism. The M166V, E828K, K861R, and P1023T variants exhibited significantly higher enzyme activity than wild-type DPD (120%, P = 0.025; 116%, P = 0.049; 130%, P = 0.0077; 138%, P = 0.048, respectively). Consistent with clinical association studies of 5-FU toxicity, the D949V substitution reduced enzyme activity by 41% (P = 0.0031). Enzyme activity was also significantly reduced for 30 additional variants, 19 of which had < 25% activity. None of those 30 variants have been previously reported to associate with 5-FU toxicity in clinical association studies, which have been conducted primarily in populations of European ancestry. Using publicly available genotype databases, we confirmed the rarity of these variants in European populations but showed that they are detected at appreciable frequencies in other populations. These data strongly suggest that testing for the reported deficient DPYD variations could dramatically improve predictive genetic tests for 5-FU sensitivity, especially in individuals of non-European descent.
Details
- Title: Subtitle
- Comparative Functional Analysis of DPYD Variants of Potential Clinical Relevance to Dihydropyrimidine Dehydrogenase Activity
- Creators
- Steven M. Offer - Mayo ClinicCroix C. Fossum - Mayo ClinicNatalie J. Wegner - Mayo ClinicAlexander J. Stuflesser - Paracelsus Medical UniversityGabriel L. Butterfield - Mayo ClinicRobert B. Diasio - Mayo Clinic
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.74(9), pp.2545-2554
- DOI
- 10.1158/0008-5472.CAN-13-2482
- PMID
- 24648345
- PMCID
- PMC4012613
- NLM abbreviation
- Cancer Res
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 10
- Grant note
- NCATS UL1 TR000135 / Mayo Clinic Center for Clinical and Translational Science P30CA015083 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) CA116964 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA NCI 5P30 CA1508337 / Mayo Clinic Cancer Center Gene Analysis Shared Resource Mayo Clinic Center for Individualized Medicine
- Language
- English
- Date published
- 05/01/2014
- Academic Unit
- Pathology
- Record Identifier
- 9984618634602771
Metrics
4 Record Views