Association of thymidylate synthase polymorphisms with gastric cancer susceptibility.
We investigated in a case-control study a possible role of thymidylate synthase gene (TS) polymorphisms for gastric cancer susceptibility. Lymphocyte genomic DNA from 134 Italian gastric cancer patients and 139 controls was used for genotyping two polymorphisms in the TS 5'-untranslated region (5'-UTR); a double (2R) or triple (3R) 28-bp repeat and a G/C polymorphism within the triple repeats allele (3G allele). Samples were also genotyped at a 6-bp deletion/insertion (del6 or ins6) polymorphism at position 1494 in the TS 3'-untranslated region (3'-UTR). Unconditional regression with odd ratios (OR) and 95% confidence intervals (CI), haplotype and linkage disequilibrium analyses were used to investigate the association of the polymorphisms with the disease. The global allelic distribution was in Hardy-Weinberg equilibrium. Genotypes with the 3G allele (2R/3G, 3C/3G, 3G/3G) were significantly more frequent in patients than controls and were associated with gastric cancer risk (OR = 2.06; 95% CI = 1.26-3.35). A significant risk was also observed for carriers of the del6 allele in the 3'-UTR. Odds ratios for combined 3G-del6/ins6 and 3G-del6/del6 genotypes were 2.59 (95% CI = 1.36-4.94) and 2.81 (95% CI = 1.22-6.64), respectively. The 3G-del6 haplotype showed a significant association with the disease (p = 0.01). Polymorphisms in the TS gene may contribute to gastric cancer susceptibility and this finding deserve further investigation in the context of novel strategies for gastric cancer prevention. In vitro, 3G genotypes have been related to high TS mRNA expression, which may underlie one of the possible etiologic mechanisms.
Graziano
Francesco
F
Medical Oncology, Hospital of Urbino, Italy. frada@tin.it
Kawakami
Kazuyuki
K
Watanabe
Go
G
Ruzzo
Annamaria
A
Humar
Bostjan
B
Santini
Daniele
D
Catalano
Vincenzo
V
Ficarelli
Rita
R
Merriman
Tony
T
Panunzi
Simona
S
Testa
Enrica
E
Cascinu
Stefano
S
Bearzi
Italo
I
Tonini
Giuseppe
G
Magnani
Mauro
M
D020413:3' Untranslated Regions / Q000235:genetics; D020121:5' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D016001:Confidence Intervals; D003596:Cytosine; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006147:Guanine; D006239:Haplotypes; D006801:Humans; D007558:Italy; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics*; D013940:Thymidylate Synthase / Q000235:genetics*
D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D006147:Guanine; D003596:Cytosine; D013940:Thymidylate Synthase