Dihydropyrimidine dehydrogenases and cytidine-deaminase gene polymorphisms as outcome predictors in resected gastric cancer patients treated with fluoropyrimidine adjuvant chemotherapy

Background and Objectives: Single nucleotide polymorphisms of dihydropyrimidine dehydrogenases gene (DPYD) induces dihydropyrimidir dehydrogenase enzyme (DPD) deficiency resulting in increased activity of 5-fluorouracil derivatives. Cytidine-deaminase gene (CDA) polymorphisms have been involved in prognosis in experimental tumours. Methods: Analysis of 50 consecutive resected gastric cancer patients who received adjuvant chemotherapy with Tegafur for polymorphisms of genes DPYD1 (A/G; Ile543Val), DPYD2 (C/T; Arg29Cys) and CDA (A/C; Lys27Gin). The status of alleles (wild-type or at least one polymorphism) was correlated with outcome and toxicity. Results: Polymorphisms frequencies wild-type/non-wild-type were 36/14 in DPYD1 (A/G; Ile543Val); 26/24 in DPYD2 (C/T; Arg29Cys); and 17/ 23 in CDA (A/C; Lys27Gin) or between homozygous/heterozygous were 39/11 in DPYD1; 33/17 in DPYD2 and 26/24 in CDA respectively. After 77 months of median follow-up (SD = 26.3), 18 patients died of tumour relapse. Better survival was observed in DPYD1 patients only, for non-wild-type over wild-type (P = 0.0214); and in patients with one or more heterozygous polymorphisms in any of the three genes tested (P = 0.0017). In 10 pts (20%) total dose was reduced by toxicity, only 3 of them were homozygous. Conclusions: Gene polymorphisms of DPYD and CDA predict survival of gastric cancer patients treated with 5-fluorouracil-based adjuvant chemotherapy.