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Carcinogenesis Advance Access published online on July 29, 2004
Carcinogenesis, doi:10.1093/carcin/bgh247
© 2004 by Oxford University Press
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Received March 9, 2004
Revised July 19, 2004
Accepted July 21, 2004

CARCINOGENESIS

Association of the thymidylate synthase polymorphisms with esophageal squamous cell carcinoma and gastric cardiac adenocarcinoma

Jianhui Zhang 1*, Yajing Cui 1, Gang Kuang 1, Yan Li 1, Na Wang 1, Rui Wang 2, Wei Guo 1, Denggui Wen 1, Lizhen Wei 1, Fengling Yu 1, Shijie Wang 3

1 Hebei Cancer Institute, Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
2 The Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
3 Hebei Cancer Institute, Hebei Medical University, Shijiazhuang 050011, Hebei Province, China; The Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang 050011, Hebei Province, China

* To whom correspondence should be addressed. E-mail: Jianhuizh{at}hotmail.com.


  Abstract

Polymorphisms in the untranslated regions (UTRs) of the thymidylate synthase (TS) gene, which may modulate TS transcription and expression, have been associated with susceptibility and prognosis of several tumors. However, their effects on the development and clinical staging of esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA) have not been assessed so far. In this study, the 28-bp tandem repeat and the G/C single nucleotide polymorphism (SNP) in the TS 5' UTR, the 6bp deletion polymorphism in the TS 3' UTR, were genotyped in 465 cancer patients (232 ESCC, 233 GCA) and 348 control subjects in North China. The genotype and allelotype distribution of the TS variants in ESCC, GCA patients and controls did not show significant difference. However, the frequency of the 6bp-/2R haplotype in ESCC and GCA patients was marginally or significantly lower than that in controls (P = 0.05 and 0.006 respectively). Thus, the 6bp-/2R significantly reduced the risk to ESCC and GCA, compared with the 6bp-/3G haplotype (OR = 0.61 and 0.48, 95% CI = 0.37-1.00 and 0.28-0.81, respectively). In addition, the 6bp+/3G haplotype in ESCC patients was also significantly less common than in controls (P = 0.002). Compared with the 6bp-/3G haplotype, the 6bp+/3G significantly reduced the risk to ESCC (OR = 0.30, 95% CI = 0.14-0.67). Moreover, the TS 2R/3G genotype frequency in ESCC patients with and without lymphatic metastasis was significantly different (27.1% versus 4.9%, P < 0.001). Therefore, the 2R/3G genotype had about 11-fold increase in the risk of lymphatic metastasis of ESCC, compared with the 3G/3G genotype (95% CI = 2.67-49.74). The results suggested that the TS polymorphisms and ESCC and GCA polymorphisms might be associated with the susceptibility to ESCC and GCA, and the 2R/3G genotype might be a candidate marker to predict the potential of lymphatic metastasis in ESCC.

Keywords: ESCC; GCA; thymidylate synthase; polymorphism; susceptibility; lymphatic metastasis.
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