Genetic variation in insulin-like growth factor-1 influences risk of colorectal cancer.

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Insulin-like Growth Factor1 (IGF1) promotes colorectal cancer growth and progression, possibly through obesity-related insulin resistance. IGF1 levels vary markedly among normal healthy individuals. Genetic factors explain at least half of the normal IGF1 variation. The relevant IGF1 polymorphisms that underlie the variation in colorectal cancer rates remain ill-defined. We have previously argued that an IGF1 polymorphism in the IGF1 promoter region, a cytosine-adenosine microsatellite (CA15-22), is not responsible for variation in IGF1 levels, but rather is in linkage disequilibrium with functional IGF1 promoter variants. We characterized putative regulatory polymorphisms in the IGF1 upstream promoter region based on a comparative genomics approach within an ethnic group of Han Chinese in a rapidly westernizing country, Singapore. We identified one common IGF1 single nucleotide polymorphism (SNP) that lies in a potentially functional element: IGF1-2995 C/A. Based on transcription factor binding site prediction algorithms, this IGF1-2995 C/A resides in a consensus domain for a transcription factor: octamer binding factor (Oct1/Oct2). The A allele destroys the predicted binding site for Oct1/Oct2. The IGF1-2995 C/A SNP (rs12579108, dbSNP build 124) is common in Han Chinese (minor allele frequency,MAF=0.36 - 0.42, this study and the Perlegen database) but is rare in European-Americans and African-Americans (MAF<0.05, Perlegen database). We examined whether this -2995 IGF1 C/A SNP predicts colorectal cancer risk among 300 cases and 1146 controls nested within the Singapore Chinese Health Study. Compared to persons not carrying a copy of the A allele (CC genotype), persons carrying at least one copy (CA or AA genotypes) had approximately 40 percent decreased risk for colorectal cancer (odds ratio, OR, for CC versus AC/AA: 0.58; 95 percent confidence interval, 95%CI: 0.44, 0.76). This association was confined to colon cancer (p for heterogeneity=0.02). In the Singapore Chinese, serum IGF1 was inversely associated with a measure of energy balance, physical activity (Probst 2003). Since IGF1 is thought to increase cancer risk by mediating the effects of obesity-related insulin resistance, we examined whether physical activity modifies the IGF1 genotype-cancer risk association. The effect of IGF1 -2995 C/A genotype was approximately two-fold stronger in physically active individuals than in physically inactive subjects (p for interaction=0.057). Taken together, these results implicate a role for insulin resistance in colonic carcinogenesis.