Genetic variations and haplotype structures of the DPYD gene encoding dihydropyrimidine dehydrogenase in Japanese and their ethnic differences

Maekawa, Keiko; Saeki, Mayumi; Saito, Yoshiro; Ozawa, Shogo; Kurose, Kouichi; Kaniwa, Nahoko; Kawamoto, Manabu; Kamatani, Naoyuki; Kato, Ken; Hamaguchi, Tetsuya; Yamada, Yasuhide; Shirao, Kuniaki; Shimada, Yasuhiro; Muto, Manabu; Doi, Toshihiko; Ohtsu, Atsushi; Yoshida, Teruhiko; Matsumura, Yasuhiro; Saijo, Nagahiro; Sawada, Jun Ichi

doi:10.1007/s10038-007-0186-6

Cited by 55 publications

(46 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Statistically significant difference between controls and the high-toxicity group was found in frequency of IVS14+1G>A carriers The DHPLC analysis performed in the low-toxicity and control groups revealed presence of five intronic variants flanking to analyzed exons (IVS9-51T>G, IVS10-15T>C, IVS12-11G>A, IVS13+39C>T, and IVS13+40A>G). All these variants of unknown significance were described previously in various populations and were not considered for further analysis in our study [12,24,25]. The strong association of IVS13+39C>T with c.1627A>G (I543V) reported in previous studies was also observed in our samples (data not shown) [16,26].…”

Section: Dpyd Alterations In the Group Of High-toxicity Patientssupporting

confidence: 68%

“…Numerous DPYD alterations were reported in published studies and case reports, however the vast majority represents missense gene variants with unknown impact on DPD enzyme activity. Moreover, the strong population differences in frequency of common DPYD gene alterations and haplotypes were described [12]. Recently, the common fragile site FRA1E was localized in DPYD gene, however the large deletions in DPYD were not studied so far [43].…”

Section: Discussionmentioning

confidence: 99%

“…Both homozygotes and heterozygotes carrying mutations in DPYD altering structure of the enzyme were shown to have decreased 5-FU catabolism [10]. Over 50 different sequence variants of DPYD were described in patients with severe toxicity following 5-FU treatment so far, and several of them are referred to as disease-causing gene alterations [10][11][12]. Despite the widely accepted disease-causing mutations (e.g.…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

Kleibl

Fidlerová²,

Kleiblová³

et al. 2009

neo

View full text Add to dashboard Cite

Alterations in dihydropyrimidine dehydrogenase gene (DPYD) coding for the key enzyme (DPD) of fluoropyrimidines (FPs) catabolism contribute to the development of serious FPs-related toxicity. We performed mutation analysis of DPYD based on cDNA sequencing in 76 predominantly colorectal cancer patients treated by FPs with early development of high (grade 3-4) hematological and/or gastrointestinal toxicity. Six previously described [85T>C (C29R), 496A>G (M166V), 775A>G (K259E), 1601G>A (S534N), 1627A>G (I543V), IVS14+1G>A, 2194G>A (V732I)] and two novel [187A>G (K63E) and 1050 G>A (R357H)] non-synonymous DPYD variants were found in 56/76 (73.7%) high-toxicity patients. Subsequently, these alterations were analyzed in 48 patients with excellent long-term tolerance of FPs and in 243 controls and were detected in 37/48 (77.1%) and 166/243 (68.3%) cases, respectively. Analysis of these alterations as risk factors for development of toxicity in pooled FPs-treated population demonstrated that C29R negatively correlated with overall gastrointestinal toxicity (OR = 0.48; 95%CI 0.23-1.0) and M166V in women protected against overall hematological toxicity and neutropenia (both OR = 0.26; 95%CI 0.07-0.89), whereas IVS14+1G>A (found in five high-toxicity patients only) increased risk of mucositis in overall population (OR = 7.0; 95%CI 1.1-44.53), and thrombocytopenia in women (OR = 10.8; 95%CI 1.24-93.98). Moreover, we identified a strong association of V732I with leucopenia (OR = 8.17; 95%CI 2.44 -27.31) and neutropenia (OR=2.78; 95% CI 1.03-7.51). Our data enabled characterization of "high risk" haplotypes (carriers of IVS14+1G>A or V732 lacking M166V) representing small (22% female and 11% male patients), population in high risk of serious hematological toxicity development, and in patients with "lower risk" that unlikely develop serious hematological toxicity [carriers of M166V without IVS14+1G>A and V732I in females (32% women), and non-carriers of C29R, M166V, IVS14+1G>A, and V732I in males (46% men)]. Our results indicate that genotyping of several DPYD variants may lead to stratification of patients with respect to the risk of serious hematological toxicity development during FPs treatment. Key words: dihydropyrimidine dehydrogenase gene [DPYD], fluoropyrimidines, 5-fluorouracil toxicity, mutation analysis, haplotypes, association study* Corresponding author † These authors contributed equally to this work.Fluoropyrimidines -5-fluorouracil (5-FU) and its derivates (e.g. capecitabine) -belong to the most frequently used anticancer drugs in treatment of solid cancers. Mechanism of action of 5-FU involves its anabolic conversions to 5-fluoropyrimidine nucleotides that exert profound inhibitory effect on thymidylate synthetase activity and interfere with RNA and DNA metabolism [1]. The development of severe toxicity is the critical complication of 5-FU-based therapy. It occurs in nearly one third of cases with progression to life-threatening complications in approximately 0.5% patients [2].About 80% of 5-FU is quickly ina...

show abstract

Section: Dpyd Alterations In the Group Of High-toxicity Patientssupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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

Kleibl

Fidlerová²,

Kleiblová³

et al. 2009

neo

View full text Add to dashboard Cite

show abstract

“…Moreover, multiple case reports (21)(22)(23)(24)(25)(26)(27), retrospective investigations (28)(29)(30), and prospective pharmacogenetic trials (31)(32)(33)(34) have shown a significantly increased inborn risk for severe, potentially lethal toxicity for IVS14þ1G>A hetero-and homozygotic patients, when given standard doses of fluoropyrimidine drugs, although a few studies could not confirm this association (35). Besides IVS14þ1G>A, more than 50 other polymorphisms in DPYD have been identified to date (36,37). Although very few of these polymorphisms have been associated with increased risk for toxicity, the clinical relevance for the majority of these polymorphisms is low or unclear.…”

Section: Introductionmentioning

confidence: 99%

Relationship between Single Nucleotide Polymorphisms and Haplotypes in DPYD and Toxicity and Efficacy of Capecitabine in Advanced Colorectal Cancer

Deenen

Tol

Burylo

et al. 2011

Clinical Cancer Research

166

156

View full text Add to dashboard Cite

Purpose: To explore the effect of dihydropyrimidine dehydrogenase (DPD) single nucleotide polymorphisms (SNP) and haplotypes on outcome of capecitabine.Experimental Design: Germline DNA was available from 568 previously untreated patients with advanced colorectal cancer participating in the CAIRO2 trial, assigned to capecitabine, oxaliplatin, and bevacizumab AE cetuximab. The coding region of dihydropyrimidine dehydrogenase gene (DPYD) was sequenced in 45 cases with grade 3 or more capecitabine-related toxicity and in 100 randomly selected controls (cohort). Most discriminating (P < 0.1) or frequently occurring (>1%) nonsynonymous SNPs were analyzed in all 568 patients. SNPs and haplotypes were associated with toxicity, capecitabine dose modifications, and survival.Results: A total of 29 SNPs were detected in the case-cohort analysis, of which 8 were analyzed in all 568 patients. Of the patients polymorphic for DPYD IVS14þ1G>A, 2846A>T, and 1236G>A, 71% (5 of 7), 63% (5 of 8), and 50% (14 of 28) developed grade 3 to 4 diarrhea, respectively, compared with 24% in the overall population. All patients polymorphic for IVS14þ1G>A developed any grade 3 to 4 toxicity, including one possibly capecitabine-related death. Because of toxicity, a mean capecitabine dose reduction of 50% was applied in IVS14þ1G>A and 25% in 2846A>T variant allele carriers. Patients were categorized into six haplotype groups: one predicted for reduced (10%), and two for increased risks (41% and 33%) for severe diarrhea. Individual SNPs were not associated with overall survival, whereas one haplotype was associated with overall survival [HR (95% CI) ¼ 0.57 (0.35-0.95)].Conclusions: DPYD IVS14þ1G>A and 2846A>T predict for severe toxicity to capecitabine, for which patients require dose reductions. Haplotypes assist in selecting patients at risk for toxicity to capecitabine.

show abstract

“…About 3%-5% of the population has a (partial) DPD deficiency, which increases the risk for 5-FU-induced severe toxicity in these individuals [120]. Currently, Ͼ50 polymorphisms in DPYD, the gene encoding DPD, have been identified [121]. The most predominant polymorphism associated with DPD deficiency is IVS14ϩ1GϾA (DPYD*2A).…”

Section: Dpdmentioning

confidence: 99%

Part 2: Pharmacogenetic Variability in Drug Transport and Phase I Anticancer Drug Metabolism

et al. 2011

View full text Add to dashboard Cite

After completing this course, the reader will be able to:1. List currently identified candidate genes involved in phase I metabolism that are potential pharmacogenetic markers in anticancer therapy.2. Describe the general effect on standard treatment of allelic variants of the candidate genes and the implications for individualized treatment.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACTEquivalent drug doses in anticancer chemotherapy may lead to wide interpatient variability in drug response reflected by differences in treatment response or in severity of adverse drug reactions. Differences in the pharmacokinetic (PK) and pharmacodynamic (PD) behavior of a drug contribute to variation in treatment outcome among patients. An important factor responsible for this variability is genetic polymorphism in genes that are involved in PK/PD processes, including drug transporters, phase I and II metabolizing enzymes, and The Oncologist CME Program is located online at http://cme.theoncologist.com/.To take the CME activity related to this article, you must be a registered user. ClinicalPharmacology:Pharmacogenetics:OpportunitiesforPatient-TailoredAnticancerTherapyThe Oncologist 2011;16:820 -834 www.TheOncologist.com by guest on May 12, 2018http://theoncologist.alphamedpress.org/ Downloaded from drug targets, and other genes that interfere with drug response. In order to achieve personalized pharmacotherapy, drug dosing and treatment selection based on genotype might help to increase treatment efficacy while reducing unnecessary toxicity. We present a series of four reviews about pharmacogenetic variability in anticancer drug treatment. This is the second review in the series and is focused on genetic variability in genes encoding drug transporters (ABCB1 and ABCG2) and phase I drug-metabolizing enzymes (CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, DPYD, CDA and BLMH) and their associations with anticancer drug treatment outcome. Based on the literature reviewed, opportunities for patient-tailored anticancer therapy are presented. The Oncologist 2011;16:820 -834

show abstract

Genetic variations and haplotype structures of the DPYD gene encoding dihydropyrimidine dehydrogenase in Japanese and their ethnic differences

Cited by 55 publications

References 28 publications

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

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

Relationship between Single Nucleotide Polymorphisms and Haplotypes in DPYD and Toxicity and Efficacy of Capecitabine in Advanced Colorectal Cancer

Part 2: Pharmacogenetic Variability in Drug Transport and Phase I Anticancer Drug Metabolism

Contact Info

Product

Resources

About