Thymidylate synthase 5'- and 3'-untranslated region polymorphisms associated with risk and progression of squamous cell carcinoma of the head and neck.
OBJECTIVE
Folate deficiency and reduced DNA repair capacity are established risk factors for squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that polymorphisms of the thymidylate synthase (TYMS) gene, which regulates a key enzyme in folate metabolism required for DNA synthesis and repair, are associated with SCCHN risk.


METHODS
In a hospital-based case-control study of 704 SCCHN cases and 1,085 controls, frequency matched by age, sex, and ethnicity, we genotyped the TSER (thymidylate synthase in the 5'-untranslated enhanced region) and TS3'UTR (thymidylate synthase in the 3'-untranslated region) polymorphisms.


RESULTS
The TS3'UTR 0bp/0bp genotype was associated with a significantly decreased risk of SCCHN [adjusted odd ratio (OR) = 0.67, 95% confidence interval (CI) = 0.47-0.94] compared with the 6bp/6bp genotype, but the TSER polymorphism had no main effect on risk of SCCHN. When we evaluated the two polymorphisms together by the number of protective alleles (the TSER 3R and TS3'UTR 0bp alleles), we found that the combined genotypes with four protective alleles (the TSER 3R3R and TS3'UTR 0bp/0bp) was associated with significantly decreased SCCHN risk (OR = 0.60, 95% CI = 0.37-0.98). In addition, the TS3'UTR 0bp genotypes were associated in an allele dose-dependent manner with a decreased risk of overall stage IV oral cancer (OR = 0.84, 95% CI = 0.52-1.34 for the 6bp/0bp genotype and OR = 0.26, 95% CI = 0.08-0.87 for the 0bp/0bp genotype; P(trend) = 0.035).


CONCLUSIONS
The TSER and TS3'UTR polymorphisms are associated with SCCHN risk. The TSER 3R and TS3'UTR 0bp alleles seemed to jointly protect against SCCHN. In particular, the 0bp allele seemed to protect against oral cancer progression.
Zhang
Zhengdong
Z
Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Shi
Qiuling
Q
Sturgis
Erich M
EM
Spitz
Margaret R
MR
Hong
Waun Ki
WK
Wei
Qingyi
Q
D020413:3' Untranslated Regions / Q000235:genetics*; D020121:5' Untranslated Regions / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012907:Smoking; D013940:Thymidylate Synthase / Q000235:genetics*
D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D013940:Thymidylate Synthase