Dihydropyrimidine dehydrogenases and cytidine-deaminase gene polymorphisms as outcome predictors in resected gastric cancer patients treated with fluoropyrimidine adjuvant chemotherapy.
OBJECTIVE
Single nucleotide polymorphisms of dihydropyrimidine dehydrogenases gene (DPYD) induces dihydropyrimidine 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.
Oncology Department, Institut Clinic de Malalties Hemato-Oncològiques (ICMHO) of Hospital Clínic, IDIBAPS (Augusto Pi i Sunyer Memorial Institute for Biomedical Research), and University of Barcelona, Barcelona, Spain.
Juan J
JJ
Grau
Miguel
M
Caballero
Mariano
M
Monzó
Carmen
C
Muñoz-García
Jose
J
Domingo-Domenech
Alfons
A
Navarro
Carlos
C
Conill
Marc
M
Campayo
Jose A
JA
Bombí
D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D003564:Cytidine Deaminase / Q000235:genetics*; D004273:DNA, Neoplasm / Q000302:isolation & purification; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005743:Gastrectomy; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008197:Lymph Node Excision; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000401:mortality; D020641:Polymorphism, Single Nucleotide; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D005641:Tegafur / Q000627:therapeutic use
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D005641:Tegafur; D042943:Dihydrouracil Dehydrogenase (NADP); D003564:Cytidine Deaminase