Associations among IRS1, IRS2, IGF1, and IGFBP3 genetic polymorphisms and colorectal cancer.
BACKGROUND
Insulin, insulin-like growth factor (IGF), and IGF binding protein (IGFBP) are involved in cell growth and proliferation and are thought to be important in the etiology of colorectal cancer. We hypothesize that genetic polymorphisms of insulin receptor substrates (IRS-1 and IRS-2), IGF-I, and IGFBP-3 alter colorectal cancer risk because of their roles in the insulin-related signaling pathway.


METHODS
Data from a population-based incident case-control study of 1,346 colon cancer cases and 1,544 population-based controls and 952 rectal cancer cases and 1,205 controls were used to evaluate associations. Genetic polymorphisms of four genes were investigated: an IGF1 CA repeat, the IGFBP3 -202 A > C, the IRS1 G972R, and the IRS2 G1057D.


RESULTS
Having at least one R allele (GR or RR) for IRS1 G972R was associated with an increased risk of colon cancer [odds ratio 1.4, 95% confidence interval (95% CI) 1.1-1.9]. The IRS2 G972R heterozygote GD genotype significantly reduced risk of colon cancer (odds ratio 0.8, 95% CI 0.6-0.9). Neither the IGF1 nor the IGFBP3 variants was associated independently with colon cancer, but there was an association when examined with IRS1. Individuals with an IRS1 R allele and IGF1 non-192 allele were at a 2-fold increased risk of colon cancer (95% CI 1.2-4.4). There was a 70% (95% CI 1.02-2.8) increased risk of colon cancer with an IRS1 R allele and the IGFBP3 AC or CC genotype. The IRS2 GD genotype reduced risk of colon cancer, except among those with an IRS1 R allele. No significant associations were seen in analyses of main effects or interactions of these variants and rectal cancer risk.


CONCLUSIONS
Both IRS1 and IRS2 variants were associated with colon cancer risk independently. Associations were slightly stronger when polymorphisms in multiple genes were evaluated in conjunction with other genes rather than individually. These data suggest that the insulin-related pathway may be important in the etiology of colon cancer but not rectal cancer.
Slattery
Martha L
ML
Health Research Center, School of Medicine, University of Utah, Salt Lake City, 84108, USA. mslatter@hrc.utah.edu
Samowitz
Wade
W
Curtin
Karen
K
Ma
Khe Ni
KN
Hoffman
Michael
M
Caan
Bette
B
Neuhausen
Susan
S
D000328:Adult; D000368:Aged; D000483:Alleles; D002140:California / Q000453:epidemiology; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D012307:Risk Factors; D011795:Surveys and Questionnaires; D014589:Utah / Q000453:epidemiology
C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D007334:Insulin-Like Growth Factor I