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TGFBR1 Haplotypes and Risk of Non–Small-Cell Lung Cancer

¹ Laboratory of Medical Genetics, School of Basic Medicine and Biological Sciences and ² Department of Surgery, The First Affiliated Hospital, Medical College of Soochow University, Suzhou, P.R. China; ³ Division of Clinical Medicine, Wuxi Third People's Hospital, Wuxi, P.R. China; ⁴ Department of Surgery, Shanghai Hospital for Pulmonary Diseases, Shanghai, P.R. China; ⁵ Department of Biostatistics, School of Public Health and ⁶ Division of Hematology/Oncology, Department of Medicine and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama

Requests for reprints: Hong-Tao Zhang, Laboratory of Medical Genetics, Medical College of Soochow University, 199 Ren'ai Road, Sino-Singapore Industrial Park, Suzhou 215123, P.R. China. Phone: 86-512-65882809; Fax: 86-512-65882809; E-mail: htzhang{at}suda.edu.cn or Boris Pasche, Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham, 1802 6th Avenue South, NP 2566, Birmingham, AL 35294-3300. Phone: 205-934-9591; Fax: 205-975-2669; E-mail: Boris.Pasche{at}ccc.uab.edu.

Key Words: NSCLC • TGFBR1 • Polymorphisms • Haplotypes • Risk

Transforming growth factor β (TGF-β) receptors are centrally involved in TGF-β–mediated cell growth and differentiation and are frequently inactivated in non–small-cell lung cancer (NSCLC). Constitutively decreased type I TGF-β receptor (TGFBR1) expression is emerging as a novel tumor-predisposing phenotype. The association of TGFBR1 haplotypes with risk for NSCLC has not yet been studied. We tested the hypothesis that single-nucleotide polymorphisms (SNP) and/or TGFBR1 haplotypes are associated with risk of NSCLC. We genotyped six TGFBR1 haplotype-tagging SNPs (htSNP) by PCR-RFLP assays and one htSNP by PCR-single-strand conformation polymorphism assay in two case-control studies. Case-control study 1 included 102 NSCLC patients and 104 healthy controls from Suzhou. Case-control study 2 included 131 patients with NSCLC and 133 healthy controls from Wuxi. Individuals included in both case-control studies were Han Chinese. Haplotypes were reconstructed according to the genotyping data and linkage disequilibrium status of these seven htSNPs. None of the htSNP was associated with NSCLC risk in either study. However, a four-marker CTGC haplotype was significantly more common among controls than among cases in both studies (P = 0.014 and P = 0.010, respectively), indicating that this haplotype is associated with decreased NSCLC risk {adjusted odds ratio [OR], 0.09 [95% confidence interval (95% CI), 0.01–0.61] and 0.11 [95% CI, 0.02–0.59], respectively}. Combined analysis of both studies shows a strong association of this four-marker haplotype with decreased NSCLC risk (adjusted OR, 0.11; 95% CI, 0.03–0.39). This is the first evidence of an association between a TGFBR1 haplotype and risk for NSCLC. [Cancer Res 2009;69(17):7046–52]