Aspirin and NSAID Chemoprevention, Gene-Environment Interactions, and Risk of Colorectal Cancer

In this issue of JAMA, Nan and colleagues1 report the results of a gene-environment interaction study examining an interactionbetween a genetic polymorphismand the regular use of aspirin or other nonsteroidal anti-inflammatory agents (NSAIDs) and the association with risk of colorectal cancer. This case-control study is scientifically noteworthy for 4 distinct reasons. First, the study advances understanding of how to conduct research designed to detect gene-environment interactions. Second, the study illustrates that interventions can be genetically targeted not just to direct treatment but also to direct preventive interventions. Third, the study provides insight into themechanistic understanding of how aspirin alters coloncancer risk. Fourth, the studyhighlights theneed to conduct implementation research to ensure clinicians are prepared to apply gene-environment research in daily practice. Nan et al and an international team of investigators from the United States, Canada, Australia, and Germany, conductedacase-control studycomparing8788coloncancercases with 8607matched controls of Europeandescent. Unlike previous studies attempting to find a genetic predictor of aspirin response that investigated only candidate genes or pathways, genome-wide analyses were performed on both cases andcontrols.2-5Genetic sequencewas imputed formost of the population, but the imputationmethodwasvalidated through direct genotyping for a subset of study participants. Imputation is awidely accepted andvalidated approach todetermining the likelygenetic sequence incasesmissingdataaboutparticular alleles. Information about recognized risk factors for colon cancer, including pattern of use of NSAIDs and aspirin, was collected for all cases and controls. Genome-wide association scanswere thenconducted to findpolymorphisms significantly associatedwith use of regular aspirin alone orwith use of aspirin plus NSAIDs in cases and controls. Regular use of aspirin, NSAIDs, or both was associated with a reduced risk of colon cancer (odds ratio [OR], 0.69 [95% CI, 0.64-0.74]), a finding consistent with the preponderance of data about the protective effect of aspirin.6-8 The key finding in this study was that this association was highly correlated with single-nucleotide polymorphism (SNP) rs2965667 and slightly less strongly with SNP rs10505806. Both SNPs are found on chromosome 12p12.3 and were highly correlated with each other. Among individuals with the rs2965667-TT genotype, regular use of aspirin, NSAIDs, or both also was significantly associated with a similar lower risk of colon cancer (OR, 0.66 [95% CI, 0.610.70]). This genotype was found in 96% of the population, so it is not surprising that the population-wide protective effect of aspirin is roughly similar to the effect in the protective genotype. Significant complexity in clinical decisions emerges from considering the 4% of the population who have a different genotype, TA or AA. Among these individuals, not only was no protective association found, but use of aspirin, NSAIDs, or both was associated with an increased risk of colon cancer (OR, 1.89 [95% CI, 1.27-2.81]). This study illustrates many aspects of modern science. First, discovering gene-environment interactions associated withpreventionof adisease requires “big science.”This study combined data from 10 observational studies that have been ongoing for more than 4 decades in 4 different countries, including some of the largest prospective studies ever conducted: theHealthProfessionalsFollow-upStudy; theNurses’ Health Study; the Prostate, Lung, Colorectal and Ovarian CancerScreeningTrial; and theWomen’sHealth Initiative.The research team includedexperts frommultiple laboratoryand clinical-based disciplines. Finding gene-environment interactions that prevent disease will demand pooling data from multiple trials or conducting large prospective trials that assess the entire genome in large populations followed up for many years. For example, the American Cancer Society’s Cancer Prevention Study 3 has enrolled 300 000 healthy individuals. As part of the study, researchers gathered blood samples from all participants and have the infrastructure to ensure decades of follow-up for this group.9 Second, clinical decisionmaking regardingpreventive interventions requires balancing the risks andbenefits of the intervention. Since the majority of individuals exposed to the interventionwill never develop the targeteddisease,most individuals cannot possibly experience a benefit, yet they are at risk forharms. Justasclinicalpractice isenteringaperiodwhen cancer treatment can be targeted based on the genetic characteristics of an individual’s cancer, studies such as thismove the field a step closer to being able to deliver preventive interventions to individualsmore likely to benefitwhilewithholding interventions fromindividualswith little likelihoodofbenefit or even risk of harm. Third, the SNPs found to be associated with higher or lower risk of colon cancer are located close to several genes known to be involved in the pathogenesis of colon cancer, including genes that affect prostaglandin synthesis and interleukin 16. This proximity supports the hypothesis that aspirin and NSAIDs exert their protective effect by altering these inflammatory mediators. Related article joi150026 Opinion