Polygenic Risk Score Has Predictive Value for Early Onset Colorectal Cancer

Polygenic Risk Score Has Predictive Value for Early Onset Colorectal Cancer

Douglas K. Rex, MD, FASGE reviewing Archambault AN, et al. Gastroenterology 2019 Dec 19.

Everyone wants to understand the underlying drivers for why early-onset colorectal cancer (CRC) is increasing and to have predictive risk scores that would allow tailored screening. Thus far, the only genetically based predictors are family history of CRC or advanced adenomas, Lynch syndrome, and polyposis syndromes. Unfortunately, the majority of early onset CRCs occur outside these risk groups.

In a case-control study involving multiple centers, 50,000 CRC cases, and 58,000 controls, a polygenic risk score (PRS) based on 95 genetic variants was tested against CRC risk.  

This PRS was associated with CRC in persons younger and older than 50 years and with and without a family history of CRC. However, the strongest association was in persons <50 years without a family history of CRC. 

For example, in persons <50 years, the highest quartile PRS had a 4.26 odds ratio (OR) for CRC compared to the lowest quartile, compared to OR 1.70 for the respective quartiles in persons <50 years with a positive family history. In a replication cohort, the PRS had an odds ratio of 1.76 for persons <50 years with a negative family history of CRC.

COMMENT
A gene-based risk panel that could be used to tailor screening and surveillance protocols for CRC in persons under age 50 is a very promising development. Such panels are only likely to improve in performance. There are many questions to answer, including performance in clinical trials and implementation issues, but the exploration of new genetic risk predictors is critically important to addressing early onset CRC.

Note to readers: At the time we reviewed this paper, its publisher noted that it was not in final form and that subsequent changes might be made.

Douglas K. Rex, MD, FASGE

CITATION(S)

Archambault AN, Su YR, Jeon J, et al. Cumulative burden of colorectal cancer-associated genetic variants is more strongly associated with early-onset vs late-onset cancer. Gastroenterology 2019 Dec 19. (Epub ahead of print) (https://doi.org/10.1053/j.gastro.2019.12.012)

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