Aspirin, NSAIDs, and colorectal cancer: possible involvement in an insulin-related pathway.
BACKGROUND
Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce risk of colorectal cancer. Although inhibition of cyclooxygenase (COX)-2 is generally thought to be the relevant mechanism, aspirin-like drugs apparently are involved in other pathways and mechanisms. We explore the associations between aspirin/NSAIDs, the insulin-related pathway, and the risk of colorectal cancer.


METHODS
Genetic polymorphisms of five genes identified as being involved in an insulin-related pathway were genotyped using data collected in a case-control study of 1346 incident colon cancer cases and 1544 population-based controls and 952 incident rectal cancer cases and 1205 controls. Genotypes assessed were the 3' untranslated region poly(A) and the intron 8 BsmI polymorphisms of the VDR gene, a CA repeat polymorphism of the IGF1 gene, the A/C polymorphism at nucleotide -202 of the IGFBP3, the Gly972Arg polymorphism of the IRS1 gene, and the Gly1057Asp polymorphism of the IRS2 gene.


RESULTS
Use of aspirin and NSAIDs was associated with a decreased risk of colorectal cancer, with slightly greater protection from NSAIDs than aspirin for rectal cancer. We observed a significant interaction between IRS1 genotype and aspirin/NSAIDs use and risk of colorectal cancer. Relative to the GR/RR IRS1 genotype, a protective effect from the GG IRS1 genotype was seen in those who did not use NSAIDs; use of NSAIDs was protective for all genotypes. These associations were especially strong for those diagnosed prior to age 65 (P interaction = 0.0006). We also observed a significant interaction between aspirin/NSAIDs use and the VDR gene. Having the SS or BB VDR genotypes reduced risk of colorectal cancer among non-aspirin/NSAID users; however, aspirin/NSAIDs reduced risk for all VDR genotypes.


CONCLUSIONS
These data support the protective effect of aspirin and NSAIDs on colorectal cancer risk. In addition, the observed interactions for aspirin/NSAIDs and IRS1 and VDR genotypes suggest that mechanisms other than COX-2 inhibition may be contributing to the protective effect of aspirin and NSAIDs on colorectal cancer risk.
Slattery
Martha L
ML
Health Research Center and Department of Pathology, School of Medicine, University of Utah, 375 Chipeta Way, Suite A, Salt Lake City, UT 84108, USA mslatter@hrc.utah.edu
Samowitz
Wade
W
Hoffman
Michael
M
Ma
Khi Ne
KN
Levin
Theodore R
TR
Neuhausen
Susan
S
D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D001241:Aspirin / Q000008:administration & dosage*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011897:Random Allocation; D011972:Receptor, Insulin / Q000235:genetics*; D012307:Risk Factors; D011795:Surveys and Questionnaires; D014589:Utah / Q000453:epidemiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011972:Receptor, Insulin; D001241:Aspirin