Carcinogenesis Advance Access originally published online on January 6, 2009
Carcinogenesis 2009 30(2):286-294; doi:10.1093/carcin/bgn283
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Sulfotransferase 1A1 haplotypes associated with oral squamous cell carcinoma susceptibility in male Taiwanese
1 Institute of Pharmacology, School of Medicine, National Yang-Ming University, No. 155, Section 2, Li-Nun Street, Taipei 112, Taiwan
2 Department of Public Health, Chang Gung University
3 Department of Otorhinolaryngology, Head and Neck Surgery, Chang Gung Memorial Hospital, Tao-Yuan 333, Taiwan
4 Department of Public Health, National Defense Medical Center, Taipei 114, Taiwan
5 Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan
6 Division of Basic Chinese Medicine, National Research Institute of Chinese Medicine, Taipei 112, Taiwan
7 Institute of Environmental and Occupational Health Sciences, School of Medicine, National Yang-Ming University, No. 155, Section 2, Li-Nun Street, Taipei 112, Taiwan
* To whom correspondence should be addressed. Tel: +886 2 2874 7848; Fax: +886 2 2875 1562; Email: tyliu{at}vghtpe.gov.tw
We have previously demonstrated that betel quid containing safrole induced DNA adducts are highly associated with the development of oral squamous cell carcinoma (OSCC) in Taiwan. Sulfotransferase (SULT) is essential for the formation of these adducts. To elucidate the effects of SULT1A1 haplotypes on OSCC susceptibility, 160 male OSCC cases and 218 age- and sex-matched controls were screened for single-nucleotide polymorphisms within the coding region of SULT1A1 by sequencing. We found that 445C>T (His149Tyr) and 507C>T polymorphisms were significantly associated with increased risk of OSCC. Based on the genotype analysis, haplotypes were constructed for 445C>T (His149Tyr), 507C>T, 600G>C and 638G>A (Arg213His) using GENECOUNTING software. After adjustment for age, cigarette smoking and betel quid chewing, we found that haplotype c containing 445C>T (His149Tyr), 507C>T or 600G>C but not 638G>A (Arg213His) variant was significantly associated with increased risk of OSCC (odds ratio, 3.24; 95% confidence interval, 1.57–6.68) when compared with the haplotype a (wild-type). We analyzed the activity in sulfonation of 2-naphthol and 1'-hydroxysafrole of recombinant His149Tyr (445C>T) variant, which led to 51 and 33% reduced activity, respectively; Arg213His (638G>A) variant led to 72 and 54% reduced activity, respectively, when compared with the wild-type. Taken together, haplotype analysis provides a novel evaluation of the SULT1A1 gene as a risk modifier on environmental carcinogen in OSCC and the association of SULT1A1 haplotypes with the risk of OSCC might be modified by betel quid chewing.
Abbreviations: CI, confidence interval; dGuo, deoxyguanosine; LC–MS/MS, liquid chromatography-tandem mass spectrometry; OSCC, oral squamous cell carcinoma; PCR, polymerase chain reaction; SNP, single-nucleotide polymorphism; SULT, sulfotransferase
Received May 28, 2008; revised November 28, 2008; accepted December 3, 2008.