Polymorphisms Of DPYD Gene Research Articles

Genetic polymorphisms of DPYD in patients with breast cancer on capecitabine therapy

Objectives: Breast cancer is the primary cause of death in Iraqi women aged 30–54 years. The study examined the relationship between (G > A) (rs3918290) and (rs55886062, T >G) DPYD gene polymorphisms, their haplotypes, and capecitabine serum concentrations in postmenopausal Iraqi women with breast cancer in postmenopausal women. During capecitabine chemotherapy.
 Methods: The study included 200 women: 100 apparently health (45-75 years old) and 100 with breast cancer (40-70 years old). This study, conducted between July and October 2022 at the oncology centre at Imam al-Hussain medical city in Kerbala, Iraq, plasma levels of Capacetabine and 5fu were measured in breast cancer patients who had been taking capecitabine for at least three months. All participants gave informed consent.
 Results: Capecitabine, and 5FU concentrations in breast cancer patients differed significantly, As the results showed, Capecitabine, and 5FU had a significantly higher concentration of them in patients with the TT allele than in those with the CC and CT alleles for the polymorphism (IVS14 + 1G > A) (rs3918290) and in patients with DPYD*13 (rs55886062) with the CC allele rather than the AA and AC alleles. Mutant allele carriers had increased Capecitabine concentrations (p<0.001).
 Conclusion: Ca15.3, serum calcium, and estradiol all exist in bodily serum, making them a potentially useful novel diagnostic biomarker for patients with breast cancer due to their high levels of stability, as well as the biological properties of tumors, such as serum calcium and estrogen.

Consensus of experts from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology for the genotyping of DPYD in cancer patients who are candidates for treatment with fluoropyrimidines

5-Fluorouracil (5-FU) and oral fluoropyrimidines, such as capecitabine, are widely used in the treatment of cancer, especially gastrointestinal tumors and breast cancer, but their administration can produce serious and even lethal toxicity. This toxicity is often related to the partial or complete deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, which causes a reduction in clearance and a longer half-life of 5-FU. It is advisable to determine if a DPD deficiency exists before administering these drugs by genotyping DPYD gene polymorphisms. The objective of this consensus of experts, in which representatives from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology participated, is to establish clear recommendations for the implementation of genotype and/or phenotype testing for DPD deficiency in patients who are candidates to receive fluoropyrimidines. The genotyping of DPYD previous to treatment classifies individuals as normal, intermediate, or poor metabolizers. Normal metabolizers do not require changes in the initial dose, intermediate metabolizers should start treatment with fluoropyrimidines at doses reduced to 50%, and poor metabolizers are contraindicated for fluoropyrimidines.

DPYD gene polymorphisms in patients with gastrointestinal tumors receiving chemotherapy with 5-fluorouracil.

90 Background: Complete or partial deficiency of the DPD enzyme due to genetic polymorphisms of the DPYD gene causes acute toxicity of fluoropyrimidines, which are widely used in combination chemotherapy regimens for various malignant neoplasms. The purpose of the study: to identify polymorphisms of the DPYD gene significant for 5-fluorouracil-induced toxicity. Methods: Venous blood samples from Caucasian patients were used to identify alleles of *2А rs3918290, 5* rs1801159, *13 rs55886062 and rs67376798 DPYD by RT-PCR and direct sequencing. Inclusion criteria were: verified diagnosis of gastrointestinal tumors, age>18 years old, fluoropyrimidine-containing regimes of treatment. Results: 104 pts were included, 54% were female. Mean age-61 years. Colorectal cancer was found in 80.7% pts, non-colorectal in 19.3% pts. Hematological and non-hematological toxicity Gd.3-4 was found in 24% pts. Allele * 5rs18011595, which causes enzyme deficiency was found in 28% of patients, (frequency was 0.281) which is significantly higher than the population frequency of the allele charactering for Caucasoid population (p <0.05). Meanwhile genotyping did not reveal the *2A, *13 alleles and rs67376798 alleles in the DPYD gene. Conclusions: *5rs1801159 allele was found as the main DPYD polymorphism associated with fluoropyrimidine toxicity in Caucasian pts with gastrointestinal tumors.

1648P - A single institution review of capecitabine related acute admissions and cost analysis

BackgroundCapecitabine is an oral pro-drug of 5FU. Dihydropyrimidine dehydrogenase (DPD), an enzyme encoded by the DPYD gene, is the rate-limiting step in 5FU catabolism. Life threatening gut wall injury occurs in a significant minority of patients and can potentially be predicted in patients with specific DPYD gene polymorphisms which result in decreased enzyme activity. Presently DPYD testing is performed in a limited number of centres in the UK. We conducted a retrospective cohort study to assess the frequency and cost of admissions due to capecitabine gut wall injury. MethodsUsing our electronic health records data base patients treated with capecitabine who were admitted for 3 days or more and had a stool sample were identified from 2010 to 2017. Individual records were reviewed to identify patients who had been admitted with severe gut wall toxicity. A Patient Level Costing System (PLiCS) was used to calculate the cost of each admission. Adverse outcomes are defined as significant morbidity (Admission > 14 days) or mortality. Results2626 patients were identified over the 7 year period; 131 were admitted with a history of G2 diarrhoea. (4.9%) 40 with grade 4 toxicity (1.5%); 13 post C1, 25 post C2, 2 post C3 of treatment. Median length of stay 16 days (3 - 46 days). Medical management included loperamide (73%), codeine (45%), octreotide (17.5%) and TPN (10%) Low albumin levels (<34g/L) or neutropenia (<1*9/L) on admission was a predictor for increased length of stay and adverse outcomes. 14 patients admitted for >14 days (35%). 11 patients died due to significant toxicity (0.4% of initial patient cohort) The costs of admission in this patient group using PLiCS analysis is approximately £37,000/annum. ConclusionsPatients presenting with significant toxicity and the potential for DPYD deficiency have significantly prolonged inpatient stays, increased morbidity and mortality. Baseline bloods are a weak predictor of outcome in this patient group. DPYD testing is near cost neutral, the introduction of routine testing for DPD deficiency would allow oncologists to identify a meaningful proportion of patients at risk of significant toxicity ahead of treatment, and the ability to modify treatment plans accordingly and improve safety. Legal entity responsible for the studyLeeds Cancer Centre. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Letter regarding Zhao et al. entitled " DPYD gene polymorphisms are associated with risk and chemotherapy prognosis in pediatric patients with acute lymphoblastic leukemia".

Zhao et al. investigated the association between germline genetic polymorphisms in DPYD, the gene encoding dihydropyrimidine dehydrogenase, and (1) the risk of developing pediatric acute lymphoblastic leukemia and (2) outcome of acute lymphoblastic leukemia following the treatment with 5-fluorouracil plus oxaliplatin (FOLFOX). The authors found that the common DPYD variant c.85T>C (rs1801265, DPYD*9A) was significantly associated with (1) risk of developing pediatric acute lymphoblastic leukemia, (2) complete response rate, (3) event-free survival, and (4) treatment-related toxicity. The authors conclude that patients carrying the c.85T>C C allele have an increased risk of developing acute lymphoblastic leukemia and have inferior outcome, and that DPYD c.85T>C can be used as a guide for individualized treatment and the decision to utilize 5-fluorouracil in acute lymphoblastic leukemia patients. In our view, the published article gives rise to multiple critical issues regarding the study's rationale and the methodology used, which strongly question the validity of the authors' conclusions.

5-Fluorouracil degradation rate could predict toxicity in stages II-III colorectal cancer patients undergoing adjuvant FOLFOX.

5-Fluorouracil is commonly used for gastrointestinal cancer treatment in an adjuvant setting; however, the toxicity can lead to a reduction, delay, or discontinuation of treatment. We retrospectively investigated the association between the 5-fluorouracil degradation rate (5-FUDR) and genetic polymorphisms of TSER, DPYD, and MHTFR with toxicity in colorectal cancer patients treated with adjuvant FOLFOX. Pretreatment 5-FUDR and MTHFR A1298T or C677T, TSER, and DPYD gene polymorphisms were characterized in stages II-III colorectal cancer patients. Patients were classified into three metabolic classes according to the 5-FUDR value. Association with toxicities was evaluated retrospectively using logistic regression analysis. Overall, 126 patients were selected (35 women, 91 men). Seven patients were poor metabolizers, 116 patients were normal metabolizers and three patients were ultra-rapid metabolizers. The median 5-FUDR was 1.53 ng/ml/10 cells/min (range: 0.42-2.57 ng/ml/10 cells/min). Severe, rate-limiting toxicities (grades 3-4) were encountered in 22.2% of patients. No associations between MTHFR or TSER polymorphisms and toxicity were detected, whereas 5-FUDR showed a statistically significant association with toxicity (P=0.0047). The DPYD heterozygous mutation was detected in only one patient, who showed grade 4 hematological toxicity and a lower 5-FUDR value. The 5-FUDR value seems not to be affected by MTHFR and TSER polymorphisms. Compared with the available pharmacogenomics tests, the pretreatment evaluation of 5-FUDR increases the proportion of identified colorectal patients at high risk for severe toxicity. Thus, it appears to be a suitable pretreatment toxicity biomarker in a subgroup of patients in whom dose-intensity maintenance is the key factor.

Association and prediction of severe 5-fluorouracil toxicity with dihydropyrimidine dehydrogenase gene polymorphisms: A meta-analysis.

The aim of the present study was to evaluate the association and prediction of dihydropyrimidine dehydrogenase gene (DPYD) polymorphisms and the risk of 5-fluorouracil (5-FU) severe toxicity in cancer patients. A meta-analysis of the published literature was conducted to summarize evidence for DPYD gene polymorphisms associated with an increased risk of severe 5-FU toxicity in patients with cancer from an Asian population. Relevant literature was identified using the PubMed and Cochrane databases on April 11, 2014. Combined risk ratios and 95% confidence intervals (CIs) were calculated in a fixed-effects model. A total of 5 clinical studies were retrieved in the meta-analysis, including 764 cancer patients with DPYD gene polymorphisms who received 5-FU-based chemotherapy. Overall, DPYD gene polymorphisms were associated with the increased risk of 5-FU severe toxicity [risk ratio=2.54 (2.15-3.00); 95% CI, 19.46-84.57; P=0.0001]. In conclusion, the present meta-analysis suggested that polymorphisms of several DPYD gene polymorphisms are associated with an increased risk of severe toxic response to 5-FU.

Potential of Dihydropyrimidine Dehydrogenase Genotypes in Personalizing 5-Fluorouracil Therapy Among Colorectal Cancer Patients

Dihydropyrimidine dehydrogenase (DPD) is a pyrimidine catabolic enzyme involved in the initial and rate-limiting step of the catabolic pathway of toxic metabolites of 5-fluorouracil (5-FU). Several studies have reported that deficiency of DPD and polymorphisms of its gene are related to 5-FU toxicities and death. Association between serum concentration of 5-FU and its related toxicity has also been previously demonstrated. Hence, this study aims to understand the role of DPYD variants in serum level of 5-FU and the risk of developing toxicity to prevent adverse reactions and maximize therapy outcome for personalized medicine. A total of 26 patients comprising 3 different ethnic groups (Malay, Chinese, and Indian) diagnosed with colorectal cancer and treated with 5-FU chemotherapy regimen from local hospital were recruited. Polymerase chain reaction and denaturing high-performance liquid chromatography methods were developed to screen polymorphisms of DPYD gene. High-performance liquid chromatography-based quantification assay was developed to measure the serum concentration of 5-FU among these patients. Patients with DPYD genotypes of deficient enzyme activity had higher median serum levels of 5-FU compared with normal DPD group (median, 11.51 mcg/mL; 95% confidence interval, 10.18-16.11 versus median, 0.83 mcg/mL; 95% confidence interval, 0.55-5.90, Mann-Whitney U test; P = 0.010). Patients with neutropenia (n = 11) had significantly higher serum concentrations of 5-FU as compared with those with normal white blood cell count (n = 15) (Mann-Whitney U test, P = 0.031). Combined regression analysis showed that the predictive power of DPYD*5 (rs1801159) and 1896 T>C (rs17376848) for serum concentrations of 5-FU in the studied group was 36.6% (P = 0.04). Similarly, DPYD*5 and 1896 T>C accounted for 29.9% of the occurrences of neutropenia (analysis of variance, P = 0.017). This study revealed that DPYD*5 (rs1801159) and 1896 T>C (rs17376848) are potentially useful predictive markers of patients' responses to 5-FU chemotherapy. Pharmacogenotyping is therefore recommended to guide dosing of 5-FU and prevent neutropenia.

Pharmacogenetic Study of 5-Fluorouracil-Related Severe Toxicity in Thai Cancer Patients: A Novel SNP Detection

Objective: The objective of this study is to determine the extent of (DPYD) Dihydropyrimidine Dehydrogenase Gene] polymorphisms of Thai cancer patients who received 5-FU based chemotherapy regimens. Methods: The study was conducted a pharmacogenetic analysis to determine the polymorphisms of DPYD gene in 116. Thai cancer patients. 76 patients developed severe (grade 3-4) toxicities after receiving the first or second cycle of 5-FU based chemotherapy. The other subject group consisted of 40 patients without severe toxicity. The DNA sequencing of every amplicon was done to identify 11 mutations as reported in Asian population. The actual change of absolute neutrophil count (ANC), hematocrit, platelet and percentage of neutrophil were compared. Results: We detected 13 SNPs of which 6 SNPs were found in exons; 967G>A, 1011A>T, 1236G>A, 1774C>T, 1896T>C and 1627A>G. The other 7 SNPs were found in intron but only IVS14+1G>A is the intron splice site. We found homozygous GG of 1627A>G in 4 patients who had severe toxicities. Statistically significant difference in actual ANC change and percentage of neutrophil change in homozygous GG [P = .011 and .009] were found. The median nadir ANC of homozygous GG is 399.6 cells/mm3. This SNP has cause the amino acid change from isoleucine to valine. Novel heterozygous SNPs (967G>A, 1774C>T) that cause the amino acid change were found in two patients with severe toxicities. Conclusions: 1627A>G, 967G>A, 1774C>T and IVS14+G>A might be the cause of (DPD) Dihydro Pyrimidine Dehydrogenase deficiency in Thai patients. The further study needs to establish the functional DPD protein in this population. Ten novel SNPs were discovered in our study.

Dihydropyrimidine dehydrogenase (DPD) single nucleotide polymorphisms (SNP) in Thai patients treated with 5-FU based regimens

14537 Background: DPD deficiency is a genetic disease caused by molecular defects in the DPD gene (DPYD). Cancer patients with DPD deficiency developed severe toxicity after receiving 5-FU based chemotherapy. The objective of this study is to determine the extent of DPYD gene polymorphisms of Thai cancer patients who received 5-FU based chemotherapy regimens. Methods: We conducted a molecular analysis to determine the polymorphisms of DPYD gene in 116 Thai cancer patients. 76 patients developed severe (grade 3–4) toxicities after receiving the first or second cycle of 5-FU based chemotherapy. The other subject group consisted of 40 patients without severe toxicity. The clinical characteristics (sex, age, diagnosis, regimen and dosage) of both groups were recorded. We isolated genomic DNA from buffy coat of their peripheral blood samples then performed PCR. The DNA sequencing of every amplicon was done to identify 11 mutations as reported in Asian population. The actual change of absolute neutrophil count (ANC), hematocrit, platelet and percentage of neutrophil were compared in each SNP using Mann Whitney U test. Results: We detected 13 SNPs which 6 SNPs were found in exons; 967G>A, 1011A>T, 1236G>A, 1774C>T, 1896T>C and 1627A>G. The other 7 SNPs were found in introns but only IVS14+1G>A is the intron splice site. There have never been report in 10 SNPs; 967G>A, 1011A>T, 1236G>A, 1774C>T, IVS8–118A>G, IVS8–17A>C, IVS11–15T>C, IVS14–68T>G, IVS14+19C>A and IVS14+134G>T. We found homozygous GG of 1627A>G in 4 patients who had severe toxicities. Statistic significant in actual ANC change and percentage of neutrophil change in homozygous GG (p=.011 and .009) were found. The median nadir ANC of homozygous GG is 399.6 cells/mm3. This SNP cause the amino acid change from isoleucine to valine. Novel heterozygous SNPs (967G>A, 1774C>T) that cause the amino acid change were found in two patients with severe toxicities. Conclusions: 1627A>G, 967G>A, 1774C>T and IVS14+G>A may be the cause of DPD deficiency in Thai patients. The further study needs to establish the functional DPD protein in this population. Ten novel SNPs were discovered in our study. No significant financial relationships to disclose.