Association of Aspirin and NSAID Use With Risk of Colorectal Cancer According to Genetic Variants

Abstract

Conclusions: Regular aspirin and/or NSAID use is associated with a lower risk of colorectal cancer and is tied to specific genetic variants. Summary: There is data that suggests that the use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a lower risk of colorectal neoplasms. (Chan AT, JAMA 2005; 294:914-923 and Friis S et al, Cancer Causes Control 2009; 20:731-740 and Rothwell PM et al, Lancet 2010; 376:1741-1750) Since virtually all vascular surgical patients are treated with aspirin or other antiplatelet agents with potential anti-inflammatory actions, the association of decreased colorectal cancer risks in such patients is of potential interest to those treating vascular surgical patients. The mechanisms, however, behind the association are not well understood. Chemo prevention of cancer is not currently recommended because of the uncertainty of risk benefit profile. The authors sought to identify genetic markers that characterize individuals who may obtain differential benefit from aspirin and NSAIDs. They conducted a discover-based, genome-wide analysis of gene X environment interactions between use of aspirin, NSAIDs or both and single nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer. This was a case controlled study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia and Germany including colorectal cancer cases (N1⁄4 8634) and matched controls (N1⁄4 8553), ascertained between 1976 and 2011. All participants were of European descent. Overall regular use of aspirin and/or NSAIDs was associated with a lower risk of colorectal cancer (prevalence, 28% vs 38%; odd ratio [OR], 0.69 [95% CI, 0.64-0.74]; P 1⁄4 6.2 x 10 ) compared with nonregular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P 1⁄4 4.6 x 10 9 for interaction). Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with re2965667-TT genotype (prevalence, 28% vs 38% OR, 0.66 [95% CI, 0.61-0.70]; P 1⁄4 7.7 x 10 ) but with a higher rate risk among those with rare TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81]; P 1⁄4 .002). In case-only interaction analysis, the SNP re 16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P1⁄4 8.2 x 10 9 for interaction). Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71]; P1⁄41.9 x 10 ) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% CI, 0.78-1.20]; P 1⁄4 .76). Comment: The study is intriguing for a couple of reasons. First of all, most vascular surgical patients are treated with aspirin, by doing so we may lower the risk colorectal cancer in many of our patients. In addition, the offtarget effect of aspirin in terms of beneficial effects on colorectal cancer can be attributed to genetic variation at two highly correlated SNPs at specific chromosomes. Perhaps off target and even on target effects of other drugs such as statins will eventually be able to be correlated with specific genetic makers. Ultimately everything tends to boil down to biochemistry and genes. Identification of specific and active approaches to utilization of medications may eventually result in a more efficient use of current medications and development of more targeted and specific future medications. In the meantime our patients have another reason to take their aspirin every day.