Single nucleotide polymorphism at codon 133 of the RASSF1 gene is preferentially associated with human lung adenocarcinoma risk

The RASSF1 gene, a putative tumor suppressor gene located on human chromosome 3p21, garners much attention for the frequent allelic loss and gene silencing via promoter hypermethylation in a variety of human malignancies. An association between a single nucleotide polymorphism (SNP) at codon 133 of the RASSF1 gene, encoding either alanine (GCT) or serine (TCT), and human cancer risk remains undefined. We therefore, investigated the distribution of the Ala133Ser SNP in 101 patients with lung cancer, 63 with head and neck cancer, 72 with colorectal cancer, 56 with esophageal cancer and 110 healthy controls by polymerase chain reaction and restriction enzyme-digestion assay. The heterozygous Ala/Ser genotype was significantly more frequent in lung cancer patients than in healthy controls (P=0.028). The adjusted odds ratio (OR) for the patients with heterozygous Ala/Ser genotype as compared with the controls with the Ala/Ala genotype was 2.59 (95% confidence interval (CI); 1.11-6.04). The increased risk of the Ala/Ser genotype was found in lung cancer patients but not in other cancer patients we examined. The association was particularly strong in those lung cancer patients of male (adjusted OR; 3.33, 95% CI; 1.37-8.12), with adenocarcinoma (adjusted OR; 3.33, 95% CI; 1.36-8.15), early stages (adjusted OR; 3.42, 95% CI; 1.33-8.75) and with smoking habit (adjusted OR; 2.70, 95% CI; 1.06-6.83). These results suggest that the RASSF1 Ala133Ser SNP is associated with development of lung cancer, especially of lung adenocarcinoma. The increased risk of the heterozygous genotype is intriguing, implying a close relation with the dimerization feature of RASSF1 proteins.