Regular Aspirin Use Could Up Colorectal Cancer Risk in Some, Genomic Study Shows

Regular Aspirin Use Could Up Colorectal Cancer Risk in Some, Genomic Study Shows

March 23, 2015

While the pooled data on those who take aspirin regularly suggest its use lowers the risk of colorectal cancer, the effect varies for each individual, depending on genetic variations.

While the pooled data on those who take aspirin regularly suggest its use lowers the risk of colorectal cancer, the effect varies for each individual, depending on genetic variations.

Researchers have identified relatively uncommon variants of two genetic loci that may increase the risk of colorectal cancer in those who take aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) regularly.

The results are published in the March 17, 2015 issue of JAMA.  

Overall, regular use of aspirin or NSAIDs was associated with a 31% lower risk of colorectal cancer (P = 6.2 x10-28). The prevalence of colorectal cancer was 28% among regular aspirin or NSAID users compared to 38% among non-regular users.

Using data from five case-control and five cohort studies, Andrew Chan, MD, MPH, associate professor in the department of medicine at Harvard Medical School and Massachusetts General Hospital in Boston (see Role of Aspirin in Colorectal Cancer Prevention and Treatment), and colleagues included 8,634 colorectal cancer case patients and 8,553 matched controls who were recruited between 1976 and 2011. All participants were of European descent, and were either from the US, Canada, Australia, or Germany.

In a genome-wide analysis of single-nucleotide polymorphisms (SNPs) to identify genetic variants that may result in different colorectal cancer risk outcomes, the study authors identified two relatively uncommon genetic variants.

One SNP at chromosome 12p12.3 adjacent to the MGST1 gene showed a significant interaction with aspirin and/or NSAID use. Among those with one particular SNP genotype, "TT," colorectal cancer risk was 34% lower. But, among those with either the more rare "TA" or "AA" genotype, colorectal cancer risk was higher with aspirin and/or NSAID use (odds ratio 1.89, P = .002). In total, 4% of the individuals included on the study harbored either the TA or AA SNP. The prevalence of colorectal cancer among those with these rare SNPs who used aspirin regularly was 35% compared to those who did not harbor either of these two SNPs.

"We suspected that an individual's genetic background might influence the likelihood that he or she may benefit from aspirin use for colorectal cancer prevention," Chan told OncoTherapy Network. "It was somewhat surprising that, while we did find such differences, only less than 10% of the population appeared not to benefit."

"The markers that appeared to modify the benefit of aspirin and NSAIDs with colorectal cancer risk appear to be associated with pathways involved in inflammation and the production of proinflammatory proteins such as prostaglandins," added Chan. "Given our understanding of aspirin and NSAIDs' ability to block inhibition and prostaglandin production; our findings do appear biologically plausible."

Evidence has been accumulating that regular use of aspirin or other NSAIDs is associated with lower risk of colorectal cancer (see For Some, Aspirin Cuts Colon Cancer Risk in Half), but whether all individuals could benefit from the daily prophylaxis is not clear. Nor is the mechanism of how aspirin may act to inhibit tumor growth or initiation of tumorigenesis. Because there is not robust evidence as to which group may benefit or be potentially harmed by regular aspirin use, daily aspirin is not recommended for any individuals to help prevent colorectal cancer.

There have been small studies of specific gene candidates suspected to modify the association between regular aspirin and colorectal cancer, noted Chan, but the current study is unique in using an unbiased, genome-wide approach to find genetic markers.

Another locus near the IL16 gene on chromosome 15q25.2 also showed an interaction with aspirin and/or NSAID use and colorectal cancer risk. Regular use of these drugs was associated with a 34% lower risk of colorectal cancer among those individuals with the AA genotype at this locus. But those with one of two less common variants, AC or CC, did not have any association with aspirin and/or NSAID use and colorectal cancer (prevalence of colorectal cancer of 36% compared to 39% among those who had or did not have either of these genetic variants, P = .76). Nine percent of those analyzed for this study had either the AC or CC genetic variant.

Further validation of the SNPs identified in this current study is needed before any targeted colorectal cancer prevention strategies can be recommended, according to the study authors.

The authors are currently planning a larger study to follow up on these results that would have greater statistical power to potentially come to a conclusion about recommendations on aspirin for colorectal cancer risk reduction.

"It will be important to examine these markers in other large populations which have collected data on aspirin and NSAID use, and conducted genetic profiling.  We would also like to pursue studies examining the role of genetic factors on aspirin-associated side effects such as gastrointestinal bleeding," said Chan.