Polymorphisms in thymidylate synthase gene and susceptibility to breast cancer in a Chinese population: a case-control analysis.
BACKGROUND
Accumulative evidence suggests that low folate intake is associated with increased risk of breast cancer. Polymorphisms in genes involved in folate metabolism may influence DNA methylation, nucleotide synthesis, and thus individual susceptibility to cancer. Thymidylate synthase (TYMS) is a key enzyme that participates in folate metabolism and catalyzes the conversion of dUMP to dTMP in the process of DNA synthesis. Two potentially functional polymorphisms [a 28-bp tandem repeat in the TYMS 5'-untranslated enhanced region (TSER) and a 6-bp deletion/insertion in the TYMS 3'-untranslated region (TS 3'-UTR)] were suggested to be correlated with alteration of thymidylate synthase expression and associated with cancer risk.


METHODS
To test the hypothesis that polymorphisms of the TYMS gene are associated with risk of breast cancer, we genotyped these two polymorphisms in a case-control study of 432 incident cases with invasive breast cancer and 473 cancer-free controls in a Chinese population.


RESULTS
We found that the distribution of TS3'-UTR (1494del6) genotype frequencies were significantly different between the cases and controls (P = 0.026). Compared with the TS3'-UTR del6/del6 wild-type genotype, a significantly reduced risk was associated with the ins6/ins6 homozygous variant genotype (adjusted OR = 0.58, 95% CI = 0.35-0.97) but not the del6/ins6 genotype (OR = 1.09, 95% CI = 0.82-1.46). Furthermore, breast cancer risks associated with the TS3'-UTR del6/del6 genotype were more evident in older women, postmenopausal subjects, individuals with a younger age at first-live birth and individuals with an older age at menarche. However, there was no evidence for an association between the TSER polymorphism and breast cancer risks.


CONCLUSIONS
These findings suggest that the TS3'-UTR del6 polymorphism may play a role in the etiology of breast cancer. Further larger population-based studies as well as functional evaluation of the variants are warranted to confirm our findings.
Zhai
Xiangjun
X
Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China. xjzhai@tom.com
Gao
Jun
J
Hu
Zhibin
Z
Tang
Jinhai
J
Qin
Jianwei
J
Wang
Shui
S
Wang
Xuechen
X
Jin
Guangfu
G
Liu
Jiyong
J
Chen
Wenshen
W
Chen
Feng
F
Wang
Xinru
X
Wei
Qingyi
Q
Shen
Hongbing
H
D020413:3' Untranslated Regions / Q000235:genetics; D020121:5' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics; D016022:Case-Control Studies; D002681:China / Q000453:epidemiology; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D011110:Polymorphism, Genetic; D017698:Postmenopause; D017584:Reproductive History; D017384:Sequence Deletion; D020080:Tandem Repeat Sequences; D013936:Thymidine / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics*
D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D005492:Folic Acid; D013940:Thymidylate Synthase; D013936:Thymidine