Two cases of 5-fluorouracil toxicity linked with gene variants in the DPYD gene

Department of Clinical Genetics, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden.
Clinical biochemistry (Impact Factor: 2.28). 10/2009; 43(3):331-4. DOI: 10.1016/j.clinbiochem.2009.09.024
Source: PubMed


Dihydropyrimidine dehydrogenase (DPD) is the initial rate-limiting enzyme in endogenous pyrimidine catabolism and is responsible for the reduction of the pyrimidine analog 5-fluorouracil (5-FU). DPD deficiency is known to cause potentially lethal toxicity in patients receiving 5-FU. We here report a frequency analysis of one of the major splice-site mutations in the DPDY gene, and further two new DPYD gene variants.
Restriction fragment length polymorphism (RFLP) and DNA sequence analysis were performed on genomic DNA and mRNA.
In 400 patients that were diagnosed with cancer and were eligible for 5-FU treatment, 14 patients were found to be heterozygous for the splice-site mutation DPYD IVS14+1G>A, which corresponds to a population frequency of 3.5%. Two novel variants in the DPYD gene were identified. The first case was heterozygous for DPYD c.1796T>C (p.M599T). In the second case, we observed heterozygosity for the splice-site mutation DPYD IVS14+17A>G.
We report two new DPYD gene variants, of which DPYD c.1796T>C is potentially pathogenic, whereas DPYD IVS14+17A>G is suggested as a variant without clinical significance.

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    • "Int J Clin Exp Med 2012;5(2):186-194 DPD deficiency is responsible for about 50% of severe 5-FU-related toxicity [5]. The most common deficient allele is DYPD*9 in Chinese with the frequent of 5-14% [6] [7]. "
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    ABSTRACT: Genetic variations influence treatment outcomes in cancer patients treated with chemotherapy. Detection of pharmacogenetic markers associated with treatment response may enable doctor to plan more precise and effective treatment tailoring to individual cancer patients. A novel oligonucleotide microarray was developed to genotype 13 variations (DPYD*2, DPYD*5, DPYD*9, TYMS 6 bp Ins/Del, UGT1A1*6, UGT1A1*27, UGT1A1*28, GSTP1 Ile105Val, XRCC1 Arg399Gln, MTHFR C677T, MDR1 C3435T/A, MDR1 G2677A/T and ERCC1 C118T). The accuracy of genotypes obtained by microarray was assessed by independent sequencing. 73 patients first diagnosed with colorectal cancer (CRC) were treated with FOLFOX4 chemotherapy. All genotypes were successfully called by microarray, and were consistent with those identified by independent sequencing except two TYMS 6 bp Ins/Del genotypes. Patients with CT or TT genotype exhibited a higher probability of response to treatment than those with CC genotype. No other SNP was found to be associated with treatment response. Furthermore, these SNPs showed no associations with gastrointestinal, hematological or neurological toxicity. ERCC1 C118T may be a predictive marker of treatment response to 5-FU/platinum chemotherapy for CRC. The microarray can significantly facilitate the process of detecting genetic variations and may help doctor plan more effective medication for individual cancer patient.
    Full-text · Article · Jan 2012 · International Journal of Clinical and Experimental Medicine
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    • "The symptoms rapidly worsened and he was admitted to hospital care for 3 weeks with grade 3–4 oral mucositis and grade 3–4 diarrhea. After 1 month of recovery, the treatment was reintroduced with a 50% dose reduction, a dose he could tolerate with only minor degree of toxicity until the end of the treatment period [23]. Another patient treated with adjuvant 5-FU 500 mg/m2 i.v. and folinic acid 60 mg/m2 i.v. on days 1 and 2, every 2 weeks, experienced grade 3 severe fatigue and grade 2 watering eyes after two thirds of treatment [23]. "
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    ABSTRACT: Fluoropyrimidines, including 5-fluorouracil (5-FU), are widely used in the treatment of solid tumors and remain the backbone of many combination regimens. Despite their clinical benefit, fluoropyrimidines are associated with gastrointestinal and hematologic toxicities, which often lead to treatment discontinuation. 5-FU undergoes complex metabolism, dihydropyrimidine dehydrogenase (DPD) being the rate-limiting enzyme of inactivation of 5-FU and its prodrugs. Several studies have demonstrated significant associations between severe toxicities by fluoropyrimidines and germline polymorphisms of DPD gene. To date, more than 30 SNPs and deletions have been identified within DPD, the majority of these variants having no functional consequences on enzymatic activity. However, the identification of deficient DPD genotypes may help identify poor-metabolizer patients at risk of developing potentially life-threatening toxicities after standard doses of fluoropyrimidines.
    Full-text · Article · Sep 2010
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    ABSTRACT: 5-Fluorouracil (5-FU) is a mainstay for treating colorectal cancer, alone or more frequently as part of combination therapies. However, its efficacy/toxicity balance is often limited by the occurrence of severe toxicities, showing in about 15%-20% of patients. Several clinical reports have shown the deleterious effect of dihydropyrimidine dehydrogenase (DPD) genetic polymorphism, a condition that reduces the liver detoxification step of standard dosages of 5-FU, in patients undergoing fluoropyrimidine-based therapy. Admittedly, DPD deficiency accounts for 50%-75% of the severe and sometimes life-threatening toxicities associated with 5-FU (or oral 5-FU). However, technical consensus on the best way to identify patients with DPD deficiency before administrating 5-FU is far from being achieved. Consequently, no regulatory step has been undertaken yet to recommend DPD testing as part of routine clinical practice for securing the administration of 5-FU. This review covers the limits and achievements of the various strategies proposed so far for determining DPD status in patients scheduled for 5-FU therapy.
    Full-text · Article · Oct 2010 · Clinical Colorectal Cancer
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