Image of gut and intestines showing colorectal cancer highlighted in red.
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Two genetic variants magnify the protective effect of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) in preventing colorectal cancer, according to a study of data covering more than 70,000 people of European descent.

The findings, in the journal Science Advances, implicate two genes directly involved in signaling pathways believed to be central to the protective effect of regular aspirin use.

The pathways involve the regulation of a receptor for inflammatory prostaglandin E2 (PGE2) and those relating to processes through which normal cells are transformed into cancerous ones.

“Combined, our findings support calls for a more nuanced, precision prevention approach to specifically identify subsets of individuals likely to benefit from aspirin/NSAIDs and improve broader, one-size-fits-all recommendations,” the researchers reported.

Studies suggest that regular, long-term use of aspirin reduces the risk of colorectal cancer by 20–30%.

To examine whether genetics might affect this, David Drew, PhD, from Massachusetts General Hospital, and colleagues pooled data from 52 clinical trials, cohort and case-control studies.

Collectively, they comprised 30,806 people with colorectal cancer and 41,861 control individuals, all of European descent.

As expected, regular aspirin/NSAID use was less prevalent among people with colorectal cancer than control individuals, at a corresponding 34% versus 40%. The same was true for aspirin use alone, at 27% versus 31%, respectively.

In meta-analyses of study-specific associations, regular aspirin/NSAID use was associated with an odds ratio (OR) of 0.76 for the risk of colorectal cancer, while aspirin use alone was associated with an OR of 0.80.

The estimated risk reductions were more pronounced in case-control than cohort studies, the authors note.

They identified a statistically significant interaction between regular aspirin/NSAID use and the genetic variant rs72833769.

Regular use of aspirin/NSAIDs or aspirin only was significantly associated with a lower risk of colorectal cancer only among homozygous carriers of the common T allele, with an OR of 0.73. There was no such association for carriers of the CT or CC genotype.

The researchers also identified a second genetic variant rs350047, which is associated with the expression of PTGER4. The latter codes for a major cell surface receptor of PGE2.

The variant showed a significant interaction with aspirin-only use and a marginally significant one for aspirin/NSAID use.

The protective benefit use was seen across all genotype groups but was greatest for homozygous carriers of the T allele, with OR of 0.67 with aspirin/NSAID use and 0.69 for aspirin-use only.

The researchers note that aspirin and other non-selective NSAIDs are believed to prevent colorectal cancer by inhibiting enzymes that lead to PGE2 synthesis.

They suggest that the association between rs350047 and PGE2 provides a mechanistic link for the SNP and the effects of NSAIDs on PGE2-PTGER4 signaling. The situation for rs72833769 was less clear, but this showed evidence of involvement in PGE2-linked pathways.

“While some markers, such as rs72833769, may provide simpler, more qualitative guidance (i.e., go/no-go) for individual stratification, quantitative interaction markers, such as rs350047, will be critical to calibrating precision prevention recommendations to maximize net benefit among those more likely to benefit, particularly when they are linked to potential mechanisms of action,” the team predicted.

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