A Novel DPYD Variant Associated With Severe Toxicity of Fluoropyrimidines: Role of Pre-emptive DPYD Genotype Screening
| Autor: | Mai-Yee Luk, Victor Ho-Fun Lee, Ka O Lam, Chi C Tong, Ching W Lam |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Oncology Cancer Research medicine.medical_specialty Colorectal cancer medicine.medical_treatment precision medicine Case Report fluoropyrimidines lcsh:RC254-282 Capecitabine 03 medical and health sciences 0302 clinical medicine Internal medicine Dihydropyrimidine dehydrogenase Medicine Exome sequencing pharmacogenetics Chemotherapy novel business.industry medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens 030104 developmental biology Fluorouracil 030220 oncology & carcinogenesis DPYD variant DPYD business Pharmacogenetics medicine.drug |
| Zdroj: | Frontiers in Oncology, Vol 8 (2018) Frontiers in Oncology |
| DOI: | 10.3389/fonc.2018.00279/full |
| Popis: | Background: The fluoropyrimidine anticancer drug, especially 5- fluorouracil (5-FU) and its prodrug capecitabine are still being the backbone of chemotherapeutic regimens for colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) is the crucial enzyme in the catabolism of 5-FU. Over the past 30 years, there is substantial clinical evidence showing that DPD deficiency is strongly associated with severe and fatal fluoropyrimidine-induced toxicity. Patients and methods: A 49-year-old lady with resected stage III carcinoma of sigmoid colon was scheduled to have a course of 5-FU based adjuvant chemotherapy. She developed unexpected acute severe (grade 4) toxicity after the first cycle of chemotherapy. Genomic DNA was isolated from 3 ml peripheral blood cells for full sequencing of DPYD (the gene encoding DPD). Results: Exome sequencing confirmed that she is heterozygous for NM_000110.3: c.321+2T>C of the DPYD gene. To the best of our knowledge, this variant is a novel pathogenic splicing variant of the DPYD gene resulting in a non-functional allele. As she has a heterozygous genotype and considered having decreased DPD activity, we followed the international recommendation and restart chemotherapy with at least 50% reduction for 5-FU dose. We then titrated the 5-FU dose, and she tolerated the subsequent cycles of chemotherapy and completed the whole course of adjuvant chemotherapy. Conclusions: With a pre-emptive test on DPD deficiency before the administration of the fluoropyrimidine drugs, the aforementioned patient's life-threatening event could be avoided. This clinical utility has been confirmed by two recent large-scale studies and called for a drug label update. |
| Databáze: | OpenAIRE |
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