New advances in DPYD genotype and risk of severe toxicity under capecitabine (original) (raw)
Related papers
Cancer management and research, 2018
Severe, life-threatening adverse reactions to capecitabine sometimes occur in the treatment of solid tumors. Screening for dihydropyrimidine dehydrogenase (DPYD) deficiency is encouraged before start of treatment, but the genetic variants that are commonly analyzed often fail to explain toxicities seen in clinical practice. Here we describe the case of a 79-year-old Caucasian female with breast cancer who presented with life-threatening, rapidly increasing toxicity after 1 week of treatment with capecitabine and for whom routine genetic test resulted negative. exon sequencing found variant c.2242+1G>T at the donor splicing site of exon 19. This variant is responsible for skipping of exon 19 and subsequent generation of a non-functional DPYD enzyme. This variant has not been described previously but was found in three other members of the patient's family. With this case, we show that exon sequencing of in patients who experience marked toxicity to fluoropyrimidines and test n...
Clinical and Translational Oncology
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 ...
PLoS ONE, 2008
Background: Cancer patients carrying mutations in the dihydropyrimidine dehydrogenase gene (DPYD) have a high risk to experience severe drug-adverse effects following chemotherapy with fluoropyrimidine drugs such as 5-fluorouracil (5-FU) or capecitabine. The pretreatment detection of this impairment of pyrimidine catabolism could prevent serious, potentially lethal side effects. As known deleterious mutations explain only a limited proportion of the drug-adverse events, we systematically searched for additional DPYD variations associated with enhanced drug toxicity.
Journal of Molecular Biomarkers & Diagnosis
Gastrointestinal toxicity due to chemotherapeutic drugs is a common problem in cancer patients. Chemotherapy-related diarrhea is most commonly described with fluoropyrimidines (fluorouracil and capecitabine) and irinotecan. Fluoropyrimidines are widely used for the treatment of gastrointestinal (GI) tract tumors and also in other solid malignancies such as breast and head and neck cancers [1,2] and are relatively well tolerated, however, around 5% to 10% of the treated patients develops severe, potentially life threatening toxicity such as GI toxicity, skin toxicity, myelosuppression and neurotoxicity [3]. Early identification of patients at risk of developing fluoropyrimidines-induced toxicity by upfront screening might allow dose reduction or selection of an alternative chemotherapy regimen. The two well-studies predictive markers for fluoropyrimidines-related toxicity are dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) enzymatic activity.
International Journal of Molecular Sciences
Deficiency of dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is associated with severe toxicity induced by the anti-cancer drug 5-Fluorouracil (5-FU). DPYD genotyping of four recommended polymorphisms is widely used to predict toxicity, yet their prediction power is limited. Increasing availability of next generation sequencing (NGS) will allow us to screen rare variants, predicting a larger fraction of DPD deficiencies. Genotype–phenotype correlations were investigated by performing DPYD exon sequencing in 94 patients assessed for DPD deficiency by the 5-FU degradation rate (5-FUDR) assay. Association of common variants with 5-FUDR was analyzed with the SNPStats software. Functional interpretation of rare variants was performed by in-silico analysis (using the HSF system and PredictSNP) and literature review. A total of 23 rare variants and 8 common variants were detected. Among common variants, a significant association was found between homozygosity for the rs72...
Cancer Chemotherapy and Pharmacology, 2010
Purpose The Xuoropyrimidines have been extensively used for almost Wve decade worldwide for the treatment of solid cancers. However, severe toxicity is a major clinical problem and has been reported in association with deleterious sequence variants in dihydropyrimidine dehydrogenase (DPD) coding-gene (DPYD), causing DPD deWciency. Genetic DPD deWciency has previously been considered to be insigniWcant in the British population. The study aim was to assess the contribution of deleterious DPYD sequence variants to Xuoropyrimidine toxicity amongst British cancer patients. Methods Sequencing of the coding region of DPYD was undertaken in 47 patients (27 female, mean age 61 years), mainly with GI malignancy, experiencing grade 3 or 4 toxicity on Xuoropyrimidines according to CTCAE criteria. Results Myelotoxicity (37.5%) and diarrhoea (37.5%) were the most frequent toxicities followed by mucositis (19.6%), hand-foot syndrome (3.6%) and neurotoxicity (1.8%). 4 of 47 (8.5%) patients carried the 1905+1G>A splice site variant. All 4 cases were female and 3 of 4 suVered severe diarrhoea. A further Wve cases carried other sequence variants (2846A>T n = 4, 1679T>G n = 1). In total, 9 (19%) patients carried deWciency associated DPYD sequence variants. Conclusions Contrary to previous estimates for a UK population, genetic DPD deWciency accounts for around 19% of cases of severe Xuoropyrimidine toxicity. The inXuence of DPD deWciency is such that toxicity can be avoided by prior testing and appropriate 5-FU dose/regimen alteration.
Journal of Clinical and Basic Research (JCBR), 2023
Background: Cancer treatment using drugs metabolized by the enzymes dihydropyrimidine dehydrogenase (DPYD) and UDP-glucuronosyltransferase 1A1 (UGT1A1) results in adverse effects for some patients. This is frequently reported in cancer patients undergoing therapy with 5-fluorouracil, capecitabine, and irinotecan who have polymorphisms in the genes coding for DPYD and UGT1A1. The present study assessed the DPYD*2A and UGT1A1*28 polymorphisms in cancer patients before starting chemotherapy to identify the individuals at risk of developing an adverse drug reaction. Methods: Genomic DNA was isolated from patients and subjected to PCR amplification using specific primers to study DPYD*2A and UGT1A1*28 polymorphisms. The PCR products were assessed by Sanger sequencing for establishing the genotype. Results: Of 75 cancer patients requiring treatment with drugs metabolized by DPYD and UGT1A1, 2 (2.66%) and 12 (29.27%) were likely to have adverse reactions based on DPYD*2A and UGT1A1*28 genotyping, respectively. Conclusion: Our findings indicate that carrying out genotyping for these two polymorphisms will help a large number of patients requiring treatment with 5-fluorouracil, irinotecan, and capecitabine.