Genes in the insulin and insulin-like growth factor pathway and odds of metachronous colorectal neoplasia

Insulin and insulin-like growth factor (IGF) genes are implicated in colorectal carcinogenesis. Gene-by-gene interactions that influence the insulin/IGF pathways were hypothesized as modifiers of colorectal neoplasia risk. We built a classification tree to detect interactions in 18 IGF and insulin pathway-related genes and metachronous colorectal neoplasia among 1,439 subjects pooled from two chemoprevention trials. The probability of colorectal neoplasia was greatest (71.8%) among carriers of any A allele for rs7166348 ( IGF1R ) and AA genotype for rs1823023 ( PIK3R1 ) . In contrast, carriers of any A at rs7166348 ( IGF1R ), any G for the PIK3R1 variant, and AA for rs10426094 ( INSR ) had the lowest probability (14.3%). Logistic regression modeling showed that any A at rs7166348 ( IGF1R ) with the AA genotype at rs1823023 ( PIK3R1 ) conferred the highest odds of colorectal neoplasia (OR 3.7; 95% CI 2.2–6.5), compared with carriage of GG at rs7166348 ( IGF1R ). Conversely, any A at rs7166348 ( IGFR1 ), any G allele at rs1823023 ( PIK3R1 ), and the AA genotype at rs10426094 ( INSR ) conferred the lowest odds (OR 0.22; 95% CI 0.07–0.66). Stratifying the analysis by parent study and intervention arm showed highly consistent trends in direction and magnitude of associations, with preliminary evidence of genotype effects on measured IGF-1 levels in a subgroup of subjects. These results were compared to those from multifactor dimensionality reduction, which identified different single nucleotide polymorphisms in the same genes ( INSR and IGF1R ) as effect modifiers for colorectal neoplasia. These results support a role for genetic interactions in the insulin/IGF pathway genes in colorectal neoplasia risk.