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Genetic Variants Affect Relationship between Colorectal Cancer Risk and Aspirin Use

NEW YORK (GenomeWeb) – The decline in colorectal cancer risk that's been observed in individuals taking aspirin or related non-steroidal anti-inflammatory drugs (NSAIDs) appears to depend on the presence of two common SNPs, according to a study in the Journal of the American Medical Association.

Members of the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) projects brought together genetic and other data for more than 8,600 colorectal cancer cases and 8,500 controls enrolled through studies in the US, Canada, Australia, and Germany over roughly three decades.

As shown in the past, the team determined that regular use of aspirin or other NSAIDs corresponded with diminished colorectal cancer risk — down roughly 30 percent compared to colorectal cancer risk in the general population.

But the protective effect vanished in individuals carrying low frequency alleles at SNP sites on chromosome 12 and chromosome 15, hinting that such variants may eventually prove useful for targeting aspirin/NSAID use.

"Since these drugs are known to have serious side effects — especially gastrointestinal bleeding — determining whether certain subsets of the population might not benefit is important for our ability to tailor recommendations for individual patients," co-corresponding author Andrew Chan, a gastroenterology researcher at Massachusetts General Hospital, said in a statement.

"This study suggests that adding information about one's genetic profile might help in making that decision," Chan said. "However, it is premature to recommend genetic screening to guide clinical care, since our findings need to be validated in other populations."

The researchers relied on information for 8,634 individuals with colorectal cancer and 8,553 unaffected controls who'd been sampled for the CCFR's case-control study or through nine case-control or cohort studies done by the GECCO between 1976 and 2011.

They then performed a gene-by-environment analysis that considered individuals' directly genotyped and imputed SNPs, together with colorectal cancer diagnoses and regular use of aspirin, other NSAIDs, or both.

Overall, the team found that regular aspirin and/or NSAID use was associated with a 28 percent prevalence of colorectal cancer — down from the 38 percent prevalence described in the general population. But the analysis highlighted instances in which the drugs did not seem to confer a benefit.

For instance, regular aspirin/NSAID use was linked to lower-than-usual colorectal cancer rates in individuals carrying two copies of the thymine allele at the chromosome 12 SNP rs2965667. But for those with the much rarer thymine-adenine or adenine-adenine genotypes, colorectal cancer risk appeared somewhat higher after regular aspirin/NSAID use.

Likewise, in an analysis that focused specifically on the colorectal cancer cases, the researchers saw no aspirin/NSAID-associated dip in colorectal cancer risk amongst individuals who were either homozygous for cytosine or had one copy of cytosine and one of adenine at the chromosome 15 SNP rs16973225.

In contrast, individuals with the more common adenine-adenine genotype at rs16973225 did seem to gain some colorectal cancer risk benefit from the drugs.

The study's authors cautioned that more research is needed to verify the results in individuals from other populations. In addition, it remains to be seen whether other variants impact responses or risk associated with regular use of the drugs.

"An equally important question that … needs to be investigated is whether there are genetic influences on the likelihood that someone might be harmed by treatment with aspirin and NSAIDs," Chan noted.