Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance

Abstract

Purpose: Although single nucleotide polymorphisms (SNP) of the dihydropyrimidine dehydrogenase gene (DPYD) have been reported, which affect enzyme activity and the severity of 5-fluorouracil (5-FU) toxicity, no pretherapeutic detection has thus far been developed. We investigated 22 DPYD gene SNPs, their respective incidence, their link with grade 3 to 4 toxic side effects, and their management in practice: 9 were looked for in 487 patients, whereas 13 others were investigated in 171 patients. Patients and Methods: SNPs were detected before 5-FU-based treatment in WBC using a Pyrosequencing method. Close clinical and biological follow-up was done. Results: Five different SNPs were found in 187 patients (IVS14 + 1G>A, 2846A>T, 1679T>G, 85T>C, −1590T>C). Three hundred patients had no SNP. Forty-four patients had grade 3 to 4 toxic side effects in either the first or second cycle. Sixty percent of patients with either IVS14 + 1G>A or 2846A>T SNPs and the only patient with 1679T>G SNP experienced early grade 3 to 4 toxicity, compared with 0%, 5.5%, and 15% of those with either −1590T>C, 85T>C SNP, or no SNP, respectively. In cases with grade 3 to 4 toxicity, treatment either had to be quickly stopped, or could be safely continued with an individual dose adjustment. Sensitivity, specificity, and positive and negative predictive values of the detection of these three major SNPs as toxicity predictive factors were 0.31, 0.98, and 0.62 and 0.94, respectively. Conclusion: Pretreatment detection of three DPYD SNPs could help to avoid severe toxic side effects. This approach is suitable for clinical practice and should be compared or combined with pharmacologic approaches. In the case of dihydropyrimidine dehydrogenase deficiency, 5-FU administration often can be safely continued with an individual dose adjustment. [Mol Cancer Ther 2006;5(11):2895–904]

Genetic variations and haplotype structures of the DPYD gene encoding dihydropyrimidine dehydrogenase in Japanese and their ethnic differences

“…Its allele frequency in Japanese (0.029 in this study) and Taiwanese (0.022) (Hsiao et al 2004) was much lower than that in (Seck et al 2005;Morel et al 2006).…”

“…For example, IVS14 + 1G[A (*2) (van Kuilenburg 2004), 295_298delTCAT (Phe100SerfsX15, *7) (Seck et al 2005), 1679T[G (Ile560Ser, *13) (CollieDuguid et al 2000;Morel et al 2006) 2846A[T (Asp949Val) (Seck et al 2005;Morel et al 2006), all of which are associated with decreased DPD activities, are detected in Caucasians with allele frequencies of 0.01-0.02, 0.003, 0.001 and 0.006-0.008, respectively. However, none of them were detected in our Japanese samples, while 1003G[T (Val335Leu, *11) and 2303C[A (Thr768Lys) have been found only in Japanese, indicating that variations with clinical relevance do not overlap between Caucasians and Japanese.…”

The influence of fluorouracil outcome parameters on tolerance and efficacy in patients with advanced colorectal cancer

“…35,36 These SNPs are associated with severe DPD deficiency and a potential life-threatening toxicity under a 5-FU regimen.…”

Pharmacogenetics and biomarkers in colorectal cancer

“…58,59 The most known DPD SNPs related to grade 3 to 4 toxicities are found on chromosome 1p. They mainly consist of the polymorphisms IVS14 þ 1G-A, 2846A-T, 1679T-G and 85T-C. 60 Recently, a new SNP mutation was found at exon 5 of the DPD gene (464T-A) and was associated with a life-threatening toxicity. 44,61 It has also been reported that the TS/DPD and TP/DPD ratios are of prognostic significance in CRC.…”