Insulin-like growth factor binding protein 7 (IGFBP7) functions mostly independent of the IGF signaling pathway and acts as a tumor suppressor in multiple cancers, but roles of IGFBP7 genetic variants in cancer remains unknown. In a hospital-based study of 1065 patients with squamous cell carcinoma of head and neck (SCCHN) and 1112 cancer-free controls of non-Hispanic whites, we investigated associations between two putatively functional IGFBP7 promoter single nucleotide polymorphisms (SNPs) (-702G>C, rs11573014 and -418G>A, rs4075349) and SCCHN risk. A significantly lower SCCHN risk was observed in those subjects carrying -418AG (adjusted OR=0.82, 95% CI=0.67-0.99) and -418AG+AA (adjusted OR=0.82, 95% CI=0.69-0.99) genotypes than those carrying the -418GG genotype, but not for the -702G>C SNP. However, those subjects carrying two common homozygous genotypes of these two SNPs (-418GG and -702GG) had an increased risk (adjusted OR=1.21, 95% CI=1.00-1.46) than did those carrying variant genotypes (-418AG+AA and -702CG+CC). This increased risk was more evident in subgroups of never smokers and subjects with oral cancer. Further functional analysis showed that the IGFBP7 -418A allele had significantly higher promoter and DNA-protein binding activities than did the G allele, suggesting a tumor suppressor role of this allelic change in the SCCHN etiology. We conclude that the functional variant -418G>C in the IGFBP7 promoter is associated with reduced risk of SCCHN, likely by enhancing the IGFBP7 promoter and DNA-protein binding activities. Larger studies are needed to validate our findings.
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