Germline pharmacogenomics in patients with dihydropyrimidine dehydrogenase (DPD) deficiency.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 521-521
Author(s):  
Moh'd M. Khushman ◽  
Peter Joel Hosein ◽  
Daniel Cameron ◽  
David Roland Clarkson ◽  
Thomas Wayne Butler ◽  
...  
Keyword(s):  
Dihydropyrimidine Dehydrogenase ◽  
Nucleotide Polymorphisms ◽  
Test Results ◽  
Single Nucleotide ◽  
Gastrointestinal Malignancies ◽  
Exact Test ◽  
Dpyd Gene ◽  
Gene Testing ◽  
Grade 3 ◽  
Dose Limiting Toxicity

521 Background: DPD deficiency is a pharmacogenetic syndrome associated with dose-limiting toxicity to fluoropyrimidines. Oncologists are expected to recognize and diagnose this syndrome, as toxicities could be fatal. Over 40 single nucleotide polymorphisms (SNPs) and deletions have been identified within the DPYD gene. IVS14+1G>A (DPYD*2A) is the most common (40-50%) and best studied of these SNPs. Yet, it showed a median sensitivity of 30% and is absent in Japanese, Korean and African Americans. Overall, the data on DPYD testing is insufficient to provide enough guidance to diagnose DPD deficiency. Herein we describe our experience with germline pharmacogenomics in patients with DPD deficiency. Methods: Between 2011 and 2015, 35 patients with gastrointestinal malignancies were tested for DPYD mutations; 17 were tested after developing toxicities to treatment and 18 were tested prior to treatment. IVS14+1G>A (DPYD*2A) was tested in all patients. DPYD c.85T>C (DPYD*9A), DPYD c.1679T>G (DPYD*13A), DPYD c.-1590T>C, and DPYD c.2846A>T were tested in 24 patients (69%) only. We explored the association between DPYD mutations and fluoropyrimidine-related toxicity using Fisher’s exact test. Results: Median age was 60 years, 43% were male, 80% were Caucasian and 20% were African American. Capecitabine-based regimens (71%) and 5-Fluorouracil-based regimens (29%). 14 out of 35 patients (40%) had DPYD mutations. Grade 3 toxicities were encountered in 64% of patients with DPYD mutation and 48% of patients with no DPYD mutation. In patients who received full dose fluoropyrimidines (57% of patients with DPYD mutation and 81% of patients with no DPYD mutation), DPYD mutations were associated with a significantly higher rate of grade 3 diarrhea (p=0.026). In patients with DPYD mutation, 2 (14%) had DPYD*A2 mutation and 12 (86%) had DPYD*9A mutation. Conclusions: In patients treated with fluoropyrimidines, the rate of grade 3 diarrhea was significantly higher in patients with mutated DPYD gene. Testing for DPYD*2A alone to diagnose DPD deficiency is suboptimal. Testing for other DPYD mutation variants including DPYD*9A provides a more comprehensive approach. These data should further be validated in prospective clinical trials.

Germline pharmacogenomics of thymidylate synthase gene in patients with gastrointestinal malignancies treated with fluoropyrimidines-based chemotherapy regimens.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 545-545 ◽  
Author(s):  
Saad Awan ◽  
Girijesh K. Patel ◽  
Anu Singh Maharjan ◽  
Gwendolyn A. McMillin ◽  
William R. Taylor ◽  
...  
Keyword(s):  
Thymidylate Synthase ◽  
Promoter Region ◽  
Active Metabolite ◽  
Dihydropyrimidine Dehydrogenase ◽  
S Phase ◽  
Gastrointestinal Malignancies ◽  
Exact Test ◽  
Racial Background ◽  
Dehydrogenase Gene ◽  
Grade 3

545 Background: Fluoropyrimidines are antimetabolites that target the S phase of the cell cycle. The active metabolite, 5-fluorodeoxyuridine monophosphate inhibits thymidylate synthase (TS) enzyme, thus preventing DNA synthesis and ultimately cell death. While controversy exists in the literature, polymorphism in the promoter region of thymidylate synthase gene (TYMS) that decrease TS expression has been associated with increased fluoropyrimidines-associated toxicities. This study explored the association between polymorphism in the promoter region of TYMS gene and fluoropyrimidines-associated toxicities in patients with gastrointestinal malignancies with mixed racial background. Methods: Between 2011 and 2018, 126 patients were genotyped for TYMS. Patients with known high-risk dihydropyrimidine dehydrogenase gene variants were excluded. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institiute Common Terminology Criteria for Adverse Events (v 5.0). Fisher’s exact test was used for statistical analysis. Results: TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) were identified in 55 patients (44%). TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) were seen in 71 patients (56%). Among patients with genotypes that predict increased TS expression (N = 55), 12 patients had grade 3-4 toxicity (22%) while among patients with genotypes that predict decreased TS expression, 30 patients had grade 3-4 toxicities (42%) (P = 0.0219). Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with 2R/2R TYMS genotype had grade 3-4 toxicity (P = 0.0039) and 15 out 40 patients (38%) with 2R/3RC and 3RC/3RC TYMS genotype had grade 3-4 toxicity (P = 0.1108). Among patients with 2R/2R TYMS, Caucasians represented 61% and African Americans represented 39%. Females represented 65% of the patients. Conclusions: Polymorphism in the promoter region of TYMS gene that predict decreased TS expression due to 2R/2R variant was associated with grade 3-4 fluoropyrimidines-associated toxicities.

ABCB1, CYP3A5*3, and CYP3A4*1B SNPs and risk of toxicity with sunitinib treatment for mRCC.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 485-485
Author(s):  
Maria Bassanelli ◽  
Alessandra Felici ◽  
Michele Milella ◽  
Diana Giannarelli ◽  
Silvana Giacinti ◽  
...  
Keyword(s):  
Nucleotide Polymorphisms ◽  
Test Results ◽  
Chi Square ◽  
Metabolizing Enzymes ◽  
Single Nucleotide ◽  
Genes Encoding ◽  
Hand Foot Syndrome ◽  
Chi Square Test ◽  
Grade 3 ◽  
The Individual

485 Background: Currently there are no biomarkers to predict either toxicity or activity of targeted therapy in mRCC. The aim of this study was to correlate single nucleotide polymorphisms (SNPs) of genes encoding for efflux transporters and metabolizing enzymes with sunitinib toxicity in metastatic renal cell carcinoma (mRCC) patients (pts). Methods: We conducted an observational, retrospective analysis of 60 Caucasian pts who received sunitinib for mRCC from 2 Italian institutions. Correlation between adverse events (AE, according to CTCAE v.4.0) and 4 polymorphisms in 3 genes (ABCB1 [1236C>T, 3435C>T], CYP3A5*3 6986A>G, CYP3A4*1B-392A>G) was analyzed. SNPs were detected in blood samples using pyrosequencing technique. Association between SNPs and toxicities was evaluated using the Chi Square test. Results: 60pts (median age: 61 years; male: 63.3%) with mRCC (clear cell: 85%, other histologies: 15%) were treated with sunitinib (83.3% as first-line). The most common AE (any-grade) reported were: hypertension (85%), asthenia (83.3%), hypothyroidism (65%), anemia (61.6%), nausea/vomiting (60%), stomatitis (58.3%), diarrhoea (48.3%), neutropenia (48.3%), thrombocytopenia (46.7%), leukopenia (46.7%), hypertriglyceridemia (45%), hyperglycaemia (38.4%), hypercholesterolemia (35%), and hand-foot syndrome (35%). Treatment was discontinued and sunitinib dose was reduced due to AE in 28.3% and 61.7% of pts, respectively. The G/A-variant in CYP3A5*3 was associated with thrombocytopenia (any grade, p=0.03); homozygous C/C alleles in ABCB1 1236C>T significantly correlated with leukopenia (any grade, p=0.01), while the C/C genotype in ABCB1 3435C>T was associated with hypertension (grade≥3, p=0.05); hypertriglyceridemia showed a trend towards increased prevalence in the presence of the C allele (grade≥3, p=0.08). Conclusions: Polymorphisms in ABCB1 and CYP3A5*3 are predictive of toxicity, as hypertension, leukopenia, and thrombocytopenia in pts with mRCC treated with sunitinib. This analysis could support the selection of the more appropriate drug to the individual patient.

The Correlation Between DPYD*9A(c.85T>C) Genotype and Dihydropyrimidine Dehydrogenase Deficiency Phenotype in Patients With Gastrointestinal Malignancies Treated With Fluoropyrimidines

2019 ◽  
Vol 152 (Supplement_1) ◽  
pp. S29-S30
Author(s):  
Anu S Maharjan ◽  
Gwendolyn McMillin ◽  
Moh’d Khushman ◽  
Girijesh Patel
Keyword(s):  
Small Sample Size ◽  
Dihydropyrimidine Dehydrogenase ◽  
Small Sample ◽  
Phenotype Correlation ◽  
Gastrointestinal Malignancies ◽  
Exact Test ◽  
Genotype Phenotype Correlation ◽  
Gi Cancer ◽  
Racial Background ◽  
Grade 3

Abstract Introduction The correlation between DPYD*9A (c.85T>C) genotype and dihydropyrimidine dehydrogenase (DPD) deficiency phenotype is controversial. In a cohort of 28 patients, DPYD*9A was the most commonly diagnosed variant (46%) and there was a noticeable genotype-phenotype correlation. Here we genotyped a larger cohort of a mixed racial background to explore the incidence of DPYD*9A variant and to further study the genotype-phenotype correlation. Methods Genotyping for high-risk DPYD variants (DPYD*2A, DPYD*13, and DPYD*9B) and the DPYD*9A variant was performed on 113 patients with gastrointestinal malignancies (GI) treated with fluoropyrimidines, using TaqMan chemistry. The prevalence of different DPYD variants was further analyzed in 1,283 retrospective data from ARUP laboratories. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (v 5.0). Fisher’s exact test was used for statistical analysis. Results In total, 1,283 were retrospectively reviewed for DPYD variants. Four patients (0.31%) carried DPYD c.-1590T>C, 10 patients (0.55%) carried DPYD c.1679T>G (*13), 36 patients (2.8%) carried DPYD c.2846A>T, and 527 patients (41.1%) carried DPYD c.85T>C (*9A). In the GI cancer cohort, DPYD variants were identified in 61 patients (54%), showing similar prevalence as the retrospective analysis. Caucasians represented 54% and African Americans represented 43%. Twenty-eight patients (46%) were females. Heterozygous DPYD*9A was identified in 46 patients (41%) and homozygous DPYD*9A was identified in 11 patients (10%). DPYD*2A was identified in 3 patients and DPYD*9B was identified in 2 patients (one patient had double heterozygous *9A and *9B). Grade 3 to 4 toxicities were experienced in 26 patients with mutant DPYD*9A (3 patients had homozygous DPYD*9A) and in 20 patients with no identified DPYD mutation (P = .7035). In patients who received full-dose fluoropyrimidines (N = 85), grade 3 to 4 toxicities were experienced in 22 patients with mutant DPYD*9A (2 patients had homozygous DPYD*9A) and in 17 patients with no identified DPYD mutation (P = .8275). Conclusion In the GI cancer population, the DPYD*9A variant was identified in 54% of patients. The correlation between DPYD*9A variant and DPD clinical phenotype was not significant. The noticeable correlation that was previously reported is likely due to small sample size and selection bias.

Feasibility of implementing a pharmacist-led DPYD gene testing service for patients commencing 5-fluorouracil (5FU) or capecitabine.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18644-e18644
Author(s):  
Benjamin Lee ◽  
Sarah Glewis ◽  
Marliese Alexander ◽  
Danny Rischin ◽  
Prudence A. Francis ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Program Implementation ◽  
Dihydropyrimidine Dehydrogenase ◽  
European Medicines Agency ◽  
Buccal Swab ◽  
Dpyd Gene ◽  
Testing Service ◽  
Gene Testing ◽  
Timely Access ◽  
Grade 3

e18644 Background: Polymorphisms in the DPYD gene, which encodes for dihydropyrimidine dehydrogenase (DPD), may impair DPD metabolism of fluoropyrimidines (FP) and cause life-threatening toxicities. The European Medicines Agency (EMA) recommend testing for DPD activity before FP therapy, but the Australian Therapeutic Goods Administration and the US Food and Drug Administration do not currently recommend this. At our hospital, pre-emptive DPYD gene screening was established in response to 7 cases of severe FP-toxicity and significant challenges for timely access to the life-saving antidote, uridine triacetate (UT), in the preceding 3 years. This study assessed the feasibility of a pharmacist-led DPYD gene testing service in an Australian cancer centre. Methods: Patients planned for FP therapy, without previous FP exposure, were referred to the Clinical Pharmacogenetics (CPGx) pharmacist for consenting, before a blood or buccal swab sample was taken. An external genomics company screened for the five Clinical Pharmacogenetics Implementation Consortium (CPIC) recommended gene variants (c.1905+1G > A, c.1679T > G, c.2846A > T, c.1236G > A and c.557A > G). Dose recommendations based on CPIC guidelines and phenotype were made to the treating clinician. Patients were followed-up for toxicity (graded according to CTCAE v5.0) at 3-5 days post first FP exposure and pre-cycle 2. Results: Between 16 December 2019 and 11 December 2020, 311 patients were planned for FP therapy. Genetic testing did not occur for 13 patients, in the first two months of program implementation mostly due to unfamiliarity with procedures. Of the 298 genotyped patients (median age 59.5 years, 52.7% female, 67.8% Upper and Lower Gastrointestinal, 18.1% Breast), 274 (91.9%) were seen by the CPGx pharmacist within 1 day of referral. Median time from samples being taken to result availability was 6 days. 286 patient (96.0%) results were reported and acted upon prior to the planned cycle 1 FP commencement date. Overall, 1 patient (0.3%, 95%CI 0.1-1.9) was identified as a poor metaboliser and avoided FP therapy. Ten patients (3.4%, 95%CI 1.8-6.0) were identified as intermediate metabolisers, of which 2 patients did not receive chemotherapy due to changes in goals of care, 1 patient received only one cycle at 100% of the full dose but passed away due to disease progression, 1 patient required UT administration after cycle 2 despite 50% dose reductions for both cycles and 6 patients received an initial 50% dose reduction, where for subsequent cycles, 3 continued at this dose level, 2 had dose increases and 1 had a further dose reduction. 17 patients experienced at least one grade 3/4 toxicity pre-cycle 2; all had normal metaboliser phenotypes. Conclusions: A pharmacist-led DPYD gene testing service is feasible, with acceptable test result turnaround times and phenotype identification rates similar to that reported by the EMA.

Prevalence of DPYD gene mutations among patients receiving 5-FU therapy.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 447-447
Author(s):  
Jennifer Saam ◽  
Karla Bowles ◽  
Laurie Korst ◽  
Kendel Kline ◽  
Benjamin Roa ◽  
...  
Keyword(s):  
Dihydropyrimidine Dehydrogenase ◽  
Gene Mutations ◽  
European Ancestry ◽  
Severe Toxicity ◽  
Sequencing Data ◽  
Dpyd Gene ◽  
Commercial Laboratory ◽  
Gene Testing ◽  
Exposure Levels ◽  
Grade 3

447 Background: Dihydropyrimidine dehydrogenase (DPYD) is the major enzyme that metabolizes 5-Fluoruracil (5-FU), a component of many chemotherapy regimens. Patients with a DPYD gene mutation have higher 5-FU plasma levels, leading to a 50-60% risk of a grade 3-4 toxicity. DPYD mutations have an estimated prevalence of 3-5% in the general population, but full sequencing is rarely performed in published studies. Analyses of the largest set of full DPYD gene sequencing test results from a commercial laboratory database are presented. Methods: A set of 3,083 patients was analyzed. Patient demographics (age, gender, ethnicity) and pre-test grade 3-4 toxicity status (none, 5-FU related, other) were obtained from the test request form. Descriptive analyses were performed to estimate mutation prevalence overall, and by toxicity and ancestry classifications, as well as to characterize mutations of interest. A subset of 24 patients tested for DPYD mutations in response to high 5-FU exposure levels was also analyzed. Results: The overall DPYD mutation prevalence was 7.3%. Mutations were present in 4.7% and 10.3% of patients experiencing none and at least one 5-FU related toxicity pre-test, respectively. Among patients with toxicities pre-test, the prevalence increased from 7.8% to 31.6% for those experiencing a single to all four toxicity types. Among 5-FU related toxicities, mutation prevalence was highest (18.5%) for hematopoietic events. The previously reported founder mutation IVS14+1G>A had a relative prevalence 42.7%, but 30.9% of these mutations were seen in patients not reporting a Western/Northern European ancestry. Among the subset of patients with high 5-FU exposure levels, 29% had a DPYD mutation showing a genetic causality. Conclusions: 5-FU in chemotherapy regimens remains widespread, yet DPYD gene testing utilization remains minimal. Most testing occurs post-treatment in response to a severe toxicity rather than pre-treatment, which would permit physicians to adapt treatment and reduce toxicity risk. Compared to previous studies, this study using full sequencing data from 3083 patients provides robust estimates of DPYD mutation prevalence and helps characterize DPYD mutations of particular interest.

scholarly journals Germline pharmacogenomics of DPYD*9A (c.85T>C) variant in patients with gastrointestinal malignancies treated with fluoropyrimidines.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 598-598
Author(s):  
Moh'd M. Khushman ◽  
Girijesh K. Patel ◽  
Peter Joel Hosein ◽  
Javier Laurini ◽  
Daniel Cameron ◽  
...  
Keyword(s):  
Statistical Analysis ◽  
Clinical Phenotype ◽  
Dihydropyrimidine Dehydrogenase ◽  
Phenotype Correlation ◽  
Gastrointestinal Malignancies ◽  
Exact Test ◽  
Full Dose ◽  
Risk Variants ◽  
Grade 3 ◽  
Experienced Grade

598 Background: The correlation between DPYD*9A (c.85T > C) genotype and dihydropyrimidine dehydrogenase (DPD) deficiency clinical phenotype is controversial. Reference laboratories either did not perform DPYD*9A genotyping or have stopped DPYD*9A genotyping and limited genotyping to high-risk variants (DPYD*2A, DPYD*13 and DPYD*9B) only. This study explored DPYD*9A genotype and clinical phenotype correlation in patients with gastrointestinal (GI) malignancies treated with fluoropyrimidines. Methods: Between 2011 and 2017, 67 patients with GI malignancies were genotyped for DPYD variants. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). Fisher’s exact test was used for statistical analysis. Results: DPYD variants were identified in 17 out of 67 (25%) patients. One patient was homozygous for DPYD*9A variant and one patient was double heterozygous for DPYD*9A and DPYD*9B variants. 13/17 (76%) patients had DPYD*9A variant, 3/17 (18%) patients had DPYD*2A variant and 2/17 (12%) patient had DPYD*9B variant. Only patients genotyped prior to 2015 were genotyped for DPYD*9A variant (N = 28). Of those, 13/28 patients (46%) had DPYD*9A variant. Grade 3-4 diarrhea was associated with DPYD*9A variant in patients treated with full dose fluoropyrimidines (P = 0.0055). Conclusions: In our cohort, DPYD*9A variant was the most common diagnosed variant. The correlation between DPYD*9A genotype and DPD deficiency clinical phenotype was noticeable in patients who received full dose fluoropyrimidines as they all experienced grade 3-4 toxicities (diarrhea).

scholarly journals Avaliação das Variantes Genéticas dos Genes AMELX e ENAM na Cárie Dentária em Adolescentes

2021 ◽  
Vol 24 (5-esp.) ◽  
pp. 650-654
Author(s):  
Gabriela Paschoalini Romagni ◽  
Paula Marino Costa ◽  
Sandra Mara Maciel ◽  
Maria Paula Jacobucci ◽  
Regina Célia Poli-Frederico
Keyword(s):  
Genetic Component ◽  
World Health ◽  
Caries Experience ◽  
Nucleotide Polymorphisms ◽  
Chi Square ◽  
Single Nucleotide ◽  
Significance Level ◽  
Exact Test ◽  
Polymerase Chain ◽  
Health Organization

A doença cárie é considerada, atualmente, como biofilme sacarose dependente, entretanto, estudos recentes apontam que fatores genéticos também podem influenciar seu desenvolvimento. Variantes nos gene amelogenina (AMELX) e enamelina (ENAM), responsáveis pela formação do esmalte, têm sido propostas como potencialmente envolvidos na doença. O objetivo deste estudo foi avaliar se a ocorrência de cárie dentária em adolescentes está relacionado às variantes nos genes AMELX e ENAM. Para a avaliação da prevalência de cárie foi utilizado o índice de dentes cariados, perdidos e obturados (CPO-D), segundo critérios da Organização Mundial de Saúde. As amostras de DNA foram extraídas das células da mucosa oral. Para a análise dos polimorfismos de nucleotídeo único (SNPs) dos genes AMELX (rs17878486) e ENAM (rs7671281) foi utilizada  a técnica de amplificação de fragmentos de DNA pela reação em cadeia da polimerase foi realizada (PCR) em tempo real pelo sistema TaqMan (Applied Biosystems, Foster City, EUA). Para a análise estatística, foi utilizado o teste exato de Fisher e qui-quadrado com nível de significância de 5%. Apenas os fatores socioeconômicos influenciaram a experiência de cárie. Concluiu-se que o componente genético, na população deste estudo, não influenciou o desenvolvimento da cárie.   Palavras-chave: Polimorfismo genético. Adolescentes. Esmalte.   Abstract Caries disease is currently considered a sucrose-dependent biofilm, however recent studies indicate that a genetic component can also influence its development. Variants in the amelogenin (AMELX) and enamelin (ENAM) genes, responsible for the enamel formation, have been proposed as potentially involved in the disease. The purpose of this study was to evaluate whether the occurrence of dental caries in adolescents is related to variants in the AMELX and ENAM genes. To assess the caries prevalence, the index of decayed, missing and filled teeth (DMFT) were used, according to World Health Organization criteria. DNA samples were extracted from oral mucosa cells. For the analysis of single nucleotide polymorphisms (SNPs) of the AMELX (rs17878486) and ENAM (rs7671281) genes, the amplifying DNA fragments technique  by the polymerase chain reaction was performed (PCR) in real time by the TaqMan system (Applied Biosystems, Foster City, USA). For the statistical analysis, Fisher's exact test and chi-square were used with a 5% significance level. Only socioeconomic factors influenced the caries experience. It was concluded that the genetic component in the population of this study, did not influence the development of caries.   Keywords: Genetic polymorphism. Adolescents. Enamel.

scholarly journals Influence of Genetic Variation in COMT on Cisplatin-Induced Nephrotoxicity in Cancer Patients

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 358
Author(s):  
Bram C. Agema ◽  
Stijn L.W. Koolen ◽  
Mirjam de With ◽  
Nadia van Doorn ◽  
Niels Heersche ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Odds Ratio ◽  
Chemotherapeutic Agent ◽  
Kidney Injury ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Number Of Patients ◽  
Low Incidence ◽  
Grade 3

Cisplatin is a chemotherapeutic agent widely used for multiple indications. Unfortunately, in a substantial set of patients treated with cisplatin, dose-limiting acute kidney injury (AKI) occurs. Here, we assessed the association of 3 catechol-O-methyltransferase (COMT) single nucleotide polymorphisms (SNPs) with increased cisplatin-induced nephrotoxicity. In total, 551 patients were genotyped for the 1947 G>A (Val158Met, rs4680), c.615 + 310 C>T (rs4646316), and c.616–367 C>T (rs9332377) polymorphisms. Associations between these variants and AKI grade ≥3 were studied. The presence of a homozygous variant of c.616-367C>T was associated with a decreased occurrence of AKI grade 3 toxicity (p = 0.014, odds ratio (OR) 0.201, 95% confidence interval (CI) (0.047–0.861)). However, we could not exclude the role of dehydration as a potential cause of AKI in 25 of the 27 patients with AKI grade 3, which potentially affected the results substantially. As a result of the low incidence of AKI grade 3 in this dataset, the lack of patients with a COMT variant, and the high number of patients with dehydration, the association between COMT variants and AKI does not seem clinically relevant.

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