Prognostic role of thymidylate synthase polymorphisms in gastric cancer patients treated with surgery and adjuvant chemotherapy.
OBJECTIVE
To investigate the prognostic role of thymidylate synthase (TS) polymorphisms in gastric cancer patients treated with radical surgery and fluorouracil-based adjuvant chemotherapy.


METHODS
Ninety gastric cancer cases were identified among 187 patients previously enrolled in prospective case-control studies for disease susceptibility. Patients were genotyped for a G/C nucleotide change within a triple 28 bp variable number of tandem repeat sequence in the TS 5'-untranslated region (5'-UTR) and a 6 bp deletion in the TS 3'-untranslated region (3'-UTR). According to available functional data, patients with 5'-UTR 2R/2R, 2R/3C, 3C/3C genotypes were classified as low TS producers (5'-UTRlow) and patients with 5'-UTR 3G/3G, 3G/3C, 2R/3G genotypes as high TS producers (5'UTRhigh). Patients with 3'-UTR del6/del6 and del6/ins6 genotypes were classified as low TS producers (3'-UTRlow) and patients with 3'-UTR ins6/ins6 genotype as high TS producers (3'-UTRhigh). The prognostic analysis was based on 5'-UTR/3'-UTR combined genotypes.


RESULTS
Ten patients (11%) were 5'-UTRhigh/3'-UTRhigh, 36 patients were 5'-UTRhigh/3'-UTRlow, 19 patients were 5'-UTRlow/3'-UTRhigh, and 25 patients were 5'-UTRlow/3'-UTRlow. 5'-UTRlow/3'-UTRlow patients showed the best outcome and the threshold of statistical significance was achieved in the comparison of disease-free survival and overall survival with 5'-UTRhigh/3'-UTRlow patients and 5'-UTRhigh/3'-UTRhigh patients. The presence of at least one high TS expression genotype showed independent adverse prognostic role in multivariate analysis.


CONCLUSIONS
The prognostic role of TS polymorphisms in gastric cancer deserves further investigation because the adverse effect of high TS expression genotypes may be a relevant information to improve adjuvant chemotherapeutic strategies.
Kawakami
Kazuyuki
K
Department of Surgery, Kanazawa University School of Medicine, Kanazawa, Japan.
Graziano
Francesco
F
Watanabe
Go
G
Ruzzo
Annamaria
A
Santini
Daniele
D
Catalano
Vincenzo
V
Bisonni
Renato
R
Arduini
Federica
F
Bearzi
Italo
I
Cascinu
Stefano
S
Muretto
Pietro
P
Perrone
Giuseppe
G
Rabitti
Carla
C
Giustini
Lucio
L
Tonini
Giuseppe
G
Pizzagalli
Francesca
F
Magnani
Mauro
M
D000368:Aged; D016022:Case-Control Studies; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011379:Prognosis; D011446:Prospective Studies; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000601:surgery; D020080:Tandem Repeat Sequences; D013940:Thymidylate Synthase / Q000235:genetics*; D016896:Treatment Outcome
D013940:Thymidylate Synthase