Research Spotlight: Identifying Genetic Variants to Prevent Future Risk of Colorectal Cancer

David A. Drew, PhD, Director of Biobanking, Clinical & Translational Epidemiology Unit and Division of Gastroenterology in Department of Medicine at Massachusetts General Hospital and an Assistant Professor of Medicine at Harvard Medical School, is the first author of a recently published paper in Science Advances, Two Genome-Wide Interaction Loci Modify the Association of Nonsteroidal Anti-Inflammatory Drugs with Colorectal Cancer.

 

What Questions Were You Investigating in this Study?

We sought to identify genetic variants that would help us identify which individuals are most likely to benefit from using low-dose aspirin regularly to help prevent their future risk of colorectal cancer. This may help doctors make more accurate individualized recommendations in the future and reduce the potential harms that may be associated with taking these medications regularly.

What Did You Find?

We identified two previously undescribed genetic loci that modify the protective effect of regular aspirin/NSAID use on colorectal cancer risk.

Functional evidence presented in our investigation implicated genes directly involved in cancer-associated signaling pathways, such as prostaglandin synthesis/signaling in the case of prostaglandin receptors, which are pathways involved in cancer initiation and progression and proposed to be central targets of aspirin’s anti-cancer effects.

What are the Clinical Implications and Next Steps?

In light of the inconsistent public health recommendations for whether aspirin should be used regularly for prevention of colorectal cancer and despite the compendium of evidence supporting a possible protective effect, our findings support calls for a more nuanced, precision prevention approach to specifically identify subsets of individuals likely to benefit from aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) and improve broader, one-size-fits-all recommendations (i.e. only on the basis of age or conditioning on added risk for cardiovascular disease as has been the case for past U.S. Preventive Services Task Force recommendations.)

While some markers, like the single nucleotide polymorphism rs72833769 identified in our analysis, may provide simpler, more qualitative guidance (i.e. go/no-go) for individual benefit stratification, quantitative interaction markers that provide an estimate of the relative degree of benefit, like the single nucleotide polymorphism rs350047 identified in our analysis, 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 like those found in our study.

These findings not only help us clarify the differential anti-cancer effects associated with aspirin/NSAIDs in the general population but help us identify novel and more effective therapeutic or prevention targets.

It also helps us better understand the specific pathways individuals are on in the development of cancer that may or may not be responsive to aspirin or other NSAIDs to help guide intervention decisions.

Moreover, our results help explain using quantitative measures why different individuals may have different responses to preventive interventions, even among patients identified as likely to respond by qualitative measures.

In all, our results support a future that employs a truly precise precision prevention approach that requires the incorporation of both qualitative and quantitative genomic interaction markers of risk (like those identified here) and individual response in context of the potential tumorigenesis pathways to which an individual is particularly susceptible in addition to other individual risk factors like diet and lifestyle choices.

Paper Cited

Drew, D. A., Kim, A. E., Lin, Y., Qu, C., Morrison, J., Lewinger, J. P., Kawaguchi, E., Wang, J., Fu, Y., Zemlianskaia, N., Díez-Obrero, V., Bien, S. A., Dimou, N., Albanes, D., Baurley, J. W., Wu, A. H., Buchanan, D. D., Potter, J. D., Prentice, R. L., Harlid, S., … Gauderman, W. J. (2024). Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer. Science advances, 10(22), eadk3121. https://doi.org/10.1126/sciadv.adk3121