Association Of TGFBR1 Haplotype And Promoter Methylation Status With Non-small Cell Lung Cancer

Part 1 Association of TGFBR1 Promoter Methylation Status with Non-small Cell Lung CancerMany malignant tumor cells, including non-small cell lung cancer (NSCLC) cells, are frequently resistant to transforming growth factorβ(TGF-β)-mediated signal transduction. This refractory response might be due to reduced/loss expression of the TGF-βreceptor 1 (TGFBR1). However, little was known about connection between inactivation of the TGFBR1 gene and the presence of CpG methylated promoter in NSCLC. To investigate whether, there is an epigenetic mechanism underlying inactivation of TGFBR1 in NSCLC, we performed the immunohistochemical and DNA methylation analyzes of TGFBR1 in tumor and the paired normal tissues from 35 resection specimens. As the first report, the present study demonstrated loss or reduction of TGFBR1 expression in 11 (31.4%) of 35 NSCLC tissues, suggesting that reduced TGFBR1 expression could contribute to the development of malignant phenotype of NSCLC, even if no aberrant DNA methylated site was found at sites -362 to -142 of TGFBR1 promoter region under investigation.Part 2 Association of TGFBR1 Polymorphisms and Haplotypes with Non-small Cell Lung CancerTransforming growth factor beta (TGF-β) receptors, including TGF-βreceptor type 1 (TGFBR1), are centrally involved in TGF-β-mediated cell growth and differentiation and are frequently inactivated in non-small cell lung cancer (NSCLC) cells. The association of TGFBR1 haplotypes with risk for NSCLC has not yet been studied. We tested the hypothesis that single nucleotide polymorphisms (SNPs) and/or TGFBR1 haplotypes are associated with risk of NSCLC. We genotyped six TGFBR1 haplotype tagging SNPs (htSNPs) by PCR-restriction fragment length polymorphism (PCR-RFLP) assays and one htSNP by PCR-single strand conformation polymorphism (PCR-SSCP) assay in two case-control studies. Case-control study 1 included 102 NSCLC patients and 104 controls from Suzhou. Case-control study 2 included 131 patients with NSCLC and 133 controls from Wuxi. Individuals included in two case-control studies were Han Chinese. Haplotypes were reconstructed according to the genotyping data and linkage disequilibrium (LD) status of these seven htSNPs. None of the htSNP was associated with NSCLC risk in anyone of two case-control studies. However, a four-marker haplotype CTGC was significantly more common among controls than among cases in two case-control studies (P=0.014 and P=0.010, respectively) indicating that this haplotype is associated with decreased NSCLC risk (adjusted OR, 0.09; 95% CI, 0.01-0.61 and adjusted OR, 0.11; 95% CI, 0.02-0.59, respectively). Combined analysis of both studies shows an association of this four-marker haplotye 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.