Diet and Colorectal Cancer: Analysis of a Candidate Pathway Using SNPS, Haplotypes, and Multi-Gene Assessment.

Publication Type:

Journal Article

Source:

Nutrition and cancer, Volume 63, Issue 8, p.1226-34 (2011)

Keywords:

2011, Alleles, AMP-Activated Protein Kinases, Case-Control Studies, Center-Authored Paper, Colorectal Neoplasms, diet, Dietary Carbohydrates, Dietary Fats, Energy Intake, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Insulin Resistance, Minnesota, November 2011, Phosphatidylinositol 3-Kinases, Polymorphism, Single Nucleotide, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Public Health Sciences Division, Ribosomal Protein S6 Kinases, 70-kDa, Ribosomal Protein S6 Kinases, 90-kDa, Signal Transduction, TOR Serine-Threonine Kinases, Tumor Suppressor Proteins, Utah

Abstract:

There is considerable biologic plausibility to the hypothesis that genetic variability in pathways involved in insulin signaling and energy homeostasis may modulate dietary risk associated with colorectal cancer. We utilized data from 2 population-based case-control studies of colon (n = 1,574 cases, 1,970 controls) and rectal (n = 791 cases, 999 controls) cancer to evaluate genetic variation in candidate SNPs identified from 9 genes in a candidate pathway: PDK1, RP6KA1, RPS6KA2, RPS6KB1, RPS6KB2, PTEN, FRAP1 (mTOR), TSC1, TSC2, Akt1, PIK3CA, and PRKAG2 with dietary intake of total energy, carbohydrates, fat, and fiber. We employed SNP, haplotype, and multiple-gene analysis to evaluate associations. PDK1 interacted with dietary fat for both colon and rectal cancer and with dietary carbohydrates for colon cancer. Statistically significant interaction with dietary carbohydrates and rectal cancer was detected by haplotype analysis of PDK1. Evaluation of dietary interactions with multiple genes in this candidate pathway showed several interactions with pairs of genes: Akt1 and PDK1, PDK1 and PTEN, PDK1 and TSC1, and PRKAG2 and PTEN. Analyses show that genetic variation influences risk of colorectal cancer associated with diet and illustrate the importance of evaluating dietary interactions beyond the level of single SNPs or haplotypes when a biologically relevant candidate pathway is examined.