Evaluation of clinical value of single nucleotide polymorphisms of dihydropyrimidine dehydrogenase gene to predict 5-fluorouracil toxicity in 60 colorectal cancer patients in China

Xin Zhang, Butong Sun, Zhenxia Lu, Xin Zhang, Butong Sun, Zhenxia Lu

Abstract

Dihydropyrimidine dehydrogenase (DPD) activity could be affected by single nucleotide polymorphisms (SNPs), resulting in either no effect, partial or complete loss of DPD activity. To evaluate if SNPs of DPD can be used to predict 5-FU toxicity, we evaluated five SNPs of DPD (14G1A, G1156T, G2194A, T85C and T464A) by TaqMan real time PCR in 60 colorectal cancer patients. Clinical data demonstrated that there was higher correlation between DPD activity and toxic effects of 5-FU (p<0.05). Six patients were positive for G2194A detection, which were all heterozygous. Two patients had lower DPD activities (< 3) with higher toxic effects (≥ stage III) while one patient was also positive for T85C detection. Ten patients were positive for T85C detection. Two patients were homozygous with lower DPD activities and higher toxic effects. Two patients were positive for the T464A detection, which were heterozygous with lower DPD activity and higher toxic effects and also positive for T85C detection. These data clearly indicated that the T464A and homozygous of the T85C are stronger biomarkers to predict the 5-FU toxicity. Our study significantly indicated that the detection for G2194A, T85C and T464A could predict ~13% of 5-FU severe toxic side effects.

Keywords: 5-fluorouracil; Dihydropyrimidine-Dehydrogenase (DPD); colorectal cancer; single nucleotide polymorphism (SNP)..

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Comparisons of DPD activities between no severe (grades 0, I and II) and severe (grades III and IV) toxic groups. A. Bone marrow inhibition. The data shown are mean values ± SD. Differences between two groups are significant (Mean = 4.292, lower 95% CI = 4.092, upper 95% CI = 4.492, p<0.001 by one-way ANOVAs and Mann Withney U = 18.50, two-tailed p<0.0001). B. Gastrointestinal reaction. The data shown are mean values ± SD. Differences between two groups are significant (Mean = 4.050, lower 95% CI = 3.816, upper 95% CI = 4.284, p<0.001 by one-way ANOVAs and Mann Withney U = 149.0, two-tailed p<0.0115).
Figure 2
Figure 2
Comparisons of DPD activities between various groups. A. Between SNP negative and SNP positive. The data shown are mean values ± SD. Differences between two groups are significant (Mean = 3.125, lower 95% CI = 2.692, upper 95% CI = 3.559, p<0.001 by one-way ANOVAs and Mann Withney U = 70.0, two-tailed p<0.0001). B. Between SNP negative and two SNPs plus homozygous. The data shown are mean values ± SD. Differences between two groups are significant (Mean = 4.177, lower 95% CI = 3.966, upper 95% CI = 4.388, p<0.001 by one-way ANOVAs and Mann Withney U = 4.0, two-tailed p<0.0014). C. Between SNP negative and T85C positive. The data shown are mean values ± SD. Differences between two groups are significant (Mean = 3.467, lower 95% CI = 2.737, upper 95% CI = 4.196, p<0.006 by one-way ANOVAs and Mann Withney U = 34.0, two-tailed p<0.0033). D. Between SNP negative and G2194A positive. The data shown are mean values ± SD. Differences between two groups are significant (Mean = 3.414, lower 95% CI = 2.570, upper 95% CI = 4.258, p<0.007 by one-way ANOVAs and Mann Withney U = 36.0, two-tailed p<0.014). E. Between one SNP and two SNPa plus homozygous. The data shown are mean values ± SD. Differences between two groups are significant (Mean = 2.253, lower 95% CI = 1.886, upper 95% CI = 2.619, p<0.004 by one-way ANOVAs and Mann Withney U = 3.0, two-tailed p<0.0157).
Figure 3
Figure 3
Comparison of toxic grades between SNP positive and SNP negative patients. A. Comparison of toxic grade of bone marrow inhibition. The data shown are mean values ± SD. Differences between two groups are significant (Mean = 2.667, lower 95% CI = 2.087, upper 95% CI = 3.246, two-tailed p<0.0005 by Mann Withney analysis and Mann Withney U = 158.5). B. Comparison of toxic grade of gastrointestinal reaction. The data shown are mean values ± SD. Differences between two groups are significant (Mean = 2.533, lower 95% CI = 1.946, upper 95% CI = 3.120, two-tailed p<0.0005 by Mann Withney analysis and Mann Withney U = 196.5).

References

    1. Parkin DM, Bray F, Ferlay J. et al. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.
    1. SEER Stat Fact Sheet; colon and rectum. National Cancer Institute; .
    1. Ades S. Adjuvant chemotherapy for colon cancer in the elderly: moving from evidence to practice. Oncology. 2009;23:162–167.
    1. Tuchman M, Stoeckeler JS, Kiang DT. et al. Familial pyrimidinemia and pyrimidinuria associated with severe fluorouracil toxicity. N Engl J Med. 1985;313:245–249.
    1. Diasio RB, Beavers TL, Carpenter JT. Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity. J Clin Invest. 1988;81:47–51.
    1. Diasio RB, Johnson MR. Dihydropyrimidine dehydrogenase: its role in 5-fluorouracil clinical toxicity and tumor resistance. Clin Cancer Res. 1999;5:2672–2673.
    1. Pinedo HM, Peters GF. Fluorouracil: biochemistry and pharmacology. J Clin Oncol. 1988;6:1653–1664.
    1. Etienne MC, Lagrange JL, Dassonville O. et al. Population study of dihydropyrimidine dehydrogenase in cancer patients. J Clin Oncol. 1994;12:2248–2253.
    1. Lu Z, Zhang R, Diasio RB. Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients, and clinical implication in 5-fluorouracil chemotherapy. Cancer Res. 1993;53:5433–5438.
    1. van Kuilenburg AB, De Abreu RA, van Gennip AH. Pharmacogenetic and clinical aspects of dihydropyrimidine dehydrogenase deficiency. Ann Clin Biochem. 2003;40:41–45.
    1. Takai S, Fernandez-Salguero P, Kimura S. et al. Assignment of the human dihydropyrimidine dehydrogenase gene (DPYD) to chromosome region 1p22 by fluorescence in situ hybridization. Genomics. 1994;24:613–614.
    1. Wei X, Elizondo G, Sapone A. et al. Characterization of the human dihydropyrimidine dehydrogenase gene. Genomics. 1998;51:391–400.
    1. Van Kuilenburg AB, Vreken P, Abeling NG. et al. Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. Hum Genet. 1999;104:1–9.
    1. van Kuilenburg AB, Haasjes J, Richel DJ. 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;6:4705–4712.
    1. van Kuilenburg AB, Muller EW, Haasjes J. et al. Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil: frequency of the common IVS14+1G>A mutation causing DPD deficiency. Clin Cancer Res. 2001;7:1149–1153.
    1. van Kuilenburg AB, Dobritzsch D, Meinsma R. et al. Novel disease-causing mutations in the dihydropyrimidine dehydrogenase gene interpreted by analysis of the three-dimensional protein structure. Biochem J. 2002;364:157–163.
    1. van Kuilenburg AB, Häusler P, Schalhorn A. et al. Evaluation of 5-fluorouracil pharmacokinetics in cancer patients with a c.1905+1G>A mutation in DPYD by means of a Bayesian limited sampling strategy. Clin Pharmacokinet. 2012;51:163–174.
    1. Zhang XP, Bai ZB, Chen BA. et al. Polymorphisms of dihydropyrimidine dehydrogenase gene and clinical outcomes of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in Chinese population. Chin Med J (Engl) 2012;125:741–746.
    1. He YF, Wei W, _ Zhang X. et al. Analysis of the DPYD gene implicated in 5-fluorouracil catabolism in Chinese cancer patients. J Clin Pharm Ther. 2008;33:307–314.
    1. Mercier C, Yang C, Ciccolini J. et al. Determination of uracil/UH2 ratio as a potential surrogate for DPD status in cancer patients presenting with severe toxicities during fluoropyrimidine treatment. J Clin Oncol ASCO Annual Meeting Proceedings Part 1. 2006;24:2020.
    1. Li S, Lai H, Li Y, Zhang L, Lin T, He Y. Determination of endogenous uracil and dihydrouracil in blood of cancer patients. Chinese Journal of Clinical Pharmacy. 2005;14:345–348.
    1. World Health Orgnization. Table 1 Recommendations for grading of acute and subacute toxic effects.; In WHO Handbook for Reporting Results of Cancer Treatment. Switzerland: WHO offset publication; 1979. pp. 15–16.
    1. Meinsma R, Fernandez-Salguero P, Van Kuilenburg ABp. et al. Human polymorphism in drug metabolism: mutation in the dihydropyrimidine dehydrogenase gene results in exon skipping and thymine uracilurea. DNA Cell Biol. 1995;14:1–6.
    1. P. Vreken P, Van Kuilenburg ABP, Meinsma R, et al. Identification of a four-base deletion (delTCAT296-299) in the dihydropyrimidine dehydrogenase gene with variable clinical expression. Hum. Genet. 1997;100:263–265.
    1. Vreken P, Van Kuilenburg ABP, Meinsma R. et al. Dihydropyrimidine dehydrogenase (DPD) deficiency: identification and expression of missense mutations C29R, R886H and R235W. Hum. Genet. 1997;101:333– 338.
    1. Van Kuilenburg ABP, Vreken P, Riva D. et al. Clinical and biochemical abnormalities in a patient with dihydropyrimidine dehydrogenase deficiency due to homozygosity for the C29R mutation. J. Inherit. Metab. Dis. 1999;22:191–192.
    1. Van Kuilenburg ABP, Vreken P, Abeling NG. et al. Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. Hum. Genet. 1999;104:1–9.
    1. McLeod HL, Collie-Duguid ES, Vreken P. et al. Nomenclature for human DPYD alleles. Pharmacogenetics. 1998;8:455–459.
    1. Van Kuilenburg AB, Meinsma R, Zoetekouw L. et al. Increased risk of grade IV neutropenia after administration of 5-fluorouracil due to a dihydropyrimidine dehydrogenase deficiency: high prevalence of the IVS14+1g>a mutation. Int J Cancer. 2002;101:253–258.
    1. Robert J, Morvan VL, Smith D. et al. Predicting drug response and toxicity based on gene polymorphisms. Crit Rev Oncol Hematol. 2005;54:171–196.
    1. Kouwaki M, Hamajima N, Sumi S. et al. Identification of novel mutations in the dihydropyrimidine dehydrogenase gene in a Japanese patient with 5-fluorouracil toxicity. Clin Cancer Res. 1998;4:2999–3004.
    1. Vreken P, Van Kuilenburg AB, Meinsma R. et al. Dihydropyrimidine dehydrogenase (DPD) deficiency: identification and expression of missense mutations C29R, R886H and R235W. Hum Genet. 1997;101:333–338.
    1. Vreken P, van Kuilenburg AB, Meinsma R. et al. Dihydropyrimidine dehydrogenase deficiency: a novel mutation and expression of missense mutations in E. coli. J Inherit Metab Dis. 1998;21:276–279.
    1. Morel A, Boisdron-Celle M, Fey L. et al. 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;40:11–17.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe