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.
Grau
Juan J
JJ
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.
Caballero
Miguel
M
Monzó
Mariano
M
Muñoz-García
Carmen
C
Domingo-Domenech
Jose
J
Navarro
Alfons
A
Conill
Carlos
C
Campayo
Marc
M
Bombí
Jose A
JA
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