EPMA Journal | |
Discovery of novel mutations in the dihydropyrimidine dehydrogenase gene associated with toxicity of fluoropyrimidines and viewpoint on preemptive pharmacogenetic screening in patients | |
Romano Danesi3  Paolo Simi4  Roberto Bordonaro1  Maurizio Cantore5  Angelo Di Leo2  Angela Michelucci4  Marzia Del Re3  | |
[1] Medical Oncology Unit, Azienda Ospedaliera Garibaldi, Catania, Italy;Medical Oncology Unit, ASL4, Prato, Italy;Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, 55, Via Roma, Pisa, 56126, Italy;Cytogenetics and Molecular Genetics Unit, University Hospital, Pisa, Italy;Medical Oncology Unit, Azienda Ospedaliera Carlo Poma, Mantova, Italy | |
关键词: DPD; Fluoropyrimidines; Colorectal cancer; Toxicity; Prediction, Personalization, Medicine; | |
Others : 1224076 DOI : 10.1186/s13167-015-0039-x |
|
received in 2015-07-30, accepted in 2015-08-09, 发布年份 2015 | |
【 摘 要 】
Background
Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of the metabolic pathway of 5-fluorouracil (5-FU) and other fluoropyrimidines to inactive compounds. For this reason, severe, life-threatening toxicities may occur in patients with deficient DPD activity when administered standard doses of 5-FU and its prodrugs.
Materials and methods
We selected three patients with colorectal adenocarcinoma who displayed unexpected severe adverse reactions after treatment with 5-FU and capecitabine. To investigate the possible involvement of deficient variants of the DPD gene (DPYD), a denaturing HPLC (dHPLC) approach followed by target exon sequencing of DPYD was performed on DNA extracted from peripheral blood.
Results
Three novel non-synonymous mutations of DPYD, c.2509-2510insC, c.1801G>C, and c.680G>A, were detected in these subjects. Due to the absence of other deficient variants of DPYD and the compatibility of adverse reactions with fluoropyrimidine treatment, the novel variants were associated with a poor-metabolizer phenotype.
Conclusions
Stratification of patients on the basis of their genotype may help prevent toxicity, and the large body of evidence about the pathogenesis of fluoropyrimidine-induced adverse reactions strongly encourages the adoption of best practice recommendations to appropriately address this important clinical issue. This approach is of utmost importance within a preventive, prognostic, and personalized approach to patient care in the oncology setting.
【 授权许可】
2015 Del Re et al.
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
20150908030443835.pdf | 399KB | download |
【 参考文献 】
- [1]Walko CM, Lindley C. Capecitabine: a review. Clin Ther. 2005; 27:23-44.
- [2]Tanaka F, Fukuse T, Wada H, Fukushima M. The history, mechanism and clinical use of oral 5-fluorouracil derivative chemotherapeutic agents. Curr Pharm Biotechnol. 2000; 1:137-64.
- [3]Johnson MR, Hageboutros A, Wang K, High L, Smith JB, Diasio RB. Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil. Clin Cancer Res. 1999; 5:2006-11.
- [4]Amstutz U, Froehlich TK, Largiadèr CR. Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity. Pharmacogenomics. 2011; 12:1321-36.
- [5]Keller G, Hartmann A, Mueller J, Höfler H. Denaturing high pressure liquid chromatography (DHPLC) for the analysis of somatic p53 mutations. Lab Invest. 2001; 81:1735-7.
- [6]Saif MW, Ezzeldin H, Vance K, Sellers S, Diasio RB. DPYD*2A mutation: the most common mutation associated with DPD deficiency. Cancer Chemother Pharmacol. 2007; 60:503-7.
- [7]van Kuilenburg AB, De Abreu RA, van Gennip AH. Pharmacogenetic and clinical aspects of dihydropyrimidine dehydrogenase deficiency. Ann Clin Biochem. 2003; 40:41-5.
- [8]Kleibl Z, Fidlerova J, Kleiblova P, Kormunda S, Bilek M, Bouskova K et al.. Influence of dihydropyrimidine dehydrogenase gene (DPYD) coding sequence variants on the development of fluoropyrimidine-related toxicity in patients with high-grade toxicity and patients with excellent tolerance of fluoropyrimidine-based chemotherapy. Neoplasma. 2009; 56:303-16.
- [9]Johnson MR, Wang K, Diasio RB. Profound dihydropyrimidine dehydrogenase deficiency resulting from a novel compound heterozygote genotype. Clin Cancer Res. 2002; 8:768-74.
- [10]Collie-Duguid ESR, Etienne MC, Milano G, McLeod HL. Known variant DPYD alleles do not explain DPD deficiency in cancer patients. Pharmacogenetics. 2000; 10:217-23.
- [11]He YF, Wei W, Zhang X, Li YH, Li S, Wang FH et al.. Analysis of the DPYD gene implicated in 5-fluorouracil catabolism in Chinese cancer patients. J Clin Pharm Ther. 2008; 33:307-14.
- [12]Newbold RJ, Deery EC, Walker CE, Wilkie SE, Srinivasan N, Hunt DM et al.. The destabilization of human GCAP1 by a proline to leucine mutation might cause cone-rod dystrophy. Hum Mol Genet. 2001; 10:47-54.
- [13]Yen JL, McLeod HL. Should DPD analysis be required prior to prescribing fluoropyrimidines? Eur J Cancer. 2007; 43:1011-6.
- [14]Terrazzino S, Cargnin S, Del Re M, Danesi R, Canonico PL, Genazzani AA. DPYD IVS14+1G>A and 2846A>T genotyping for the prediction of severe fluoropyrimidine-related toxicity: a meta-analysis. Pharmacogenomics. 2013; 14:1255-72.
- [15]Innocenti F. DPYD variants to predict 5-FU toxicity: the ultimate proof. J Natl Cancer Inst. 2014;106. doi:10.1093/jnci/dju351.
- [16]Goldstein DA, Shaib WL, Flowers CR. Costs and effectiveness of genomic testing in the management of colorectal cancer. Oncology (Williston Park). 2015; 29(3):175-83.
- [17]Golubnitschaja O, Costigliola V. General report & recommendations in predictive, preventive and personalised medicine 2012: white paper of the European Association for Predictive, Preventive and Personalised Medicine. EPMA J. 2012; 3:1-53.
- [18]Zhang H, Li YM, Zhang H, Jin X. DPYD*5 gene mutation contributes to the reduced DPYD enzyme activity and chemotherapeutic toxicity of 5-FU: results from genotyping study on 75 gastric carcinoma and colon carcinoma patients. Med Oncol. 2007; 24:251-8.
- [19]van Kuilenburg AB, Haasjes J, Meinsma R, Waterham HR, Vreken P, van Gennip AH. Dihydropyrimidine dehydrogenase (DPD) deficiency: novel mutations in the DPD gene. Adv Exp Med Biol. 2000; 486:247-50.
- [20]Morel A, Boisdron-Celle M, Fey L, Lainé-Cessac P, Gamelin E. Identification of a novel mutation in the dihydropyrimidine dehydrogenase gene in a patient with a lethal outcome following 5-fluorouracil administration and the determination of its frequency in a population of 500 patients with colorectal carcinoma. Clin Biochem. 2007; 40:11-7.
- [21]Gross E, Busse B, Riemenschneider M, Neubauer S, Seck K, Klein HG et al.. Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients. PLoS One. 2008; 3:e4003.
- [22]Shahrokni A, Rajebi MR, Harold L, Saif MW. Cardiotoxicity of 5-fluorouracil and capecitabine in a pancreatic cancer patient with a novel mutation in the dihydropyrimidine dehydrogenase gene. JOP. 2009; 10:215-20.
- [23]Vreken P, van Kuilenburg ABP, Meinsma R, De Abreu RA, VanGennip AH. Dihydropyrimidine dehydrogenase (DPD) deficiency: identification and expression of missense mutations C29R, R886H and R235W. Hum Genet. 1997; 101:333-8.
- [24]Morel A, Boisdron-Celle M, Fey L, Soulie P, Craipeau MC, Traore S et al.. Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5‐fluorouracil tolerance. Mol Cancer Ther. 2006; 5:2895-904.
- [25]Gross E, Ullrich T, Seck K, Mueller V, de Wit M, von Schilling C et al.. Detailed analysis of five mutations in dihydropyrimidine dehydrogenase detected in cancer patients with 5‐fluorouracil‐related side effects. Hum Mutat. 2003; 22:498-506.
- [26]van Kuilenburg AB, Haasjes J, Richel DJ, Zoetekouw L, Van Lenthe H, De Abreu RA et al.. Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin Cancer Res. 2000; 6:4705-12.
- [27]Mercier C, Ciccolini J. Severe or lethal toxicities upon capecitabine intake: is DPYD genetic polymorphism the ideal culprit? Trends Pharmacol Sci. 2007; 28:597-8.
- [28]Ben Fredj R, Gross E, Chouchen L, B'Chir F, Ben Ahmed S, Neubauer S et al.. Mutational spectrum of dihydropyrimidine dehydrogenase gene (DPYD) in the Tunisian population. C R Biol. 2007; 330:764-9.