Improving Consistency in Colorectal Cancer Genetic Risk Assessment and Return of Results Through an Integrated Polygenic Risk Score

Polygenic risk score integrating 28 published scores (stPRS-CRC)

Published colorectal cancer polygenic risk scores (PRS) show similar population-level performance but often assign different risk classifications to the same individuals, which complicates clinical implementation and return of results. The authors built a stable score, stPRS-CRC, by integrating 28 published PRS with PRSmix in the All of Us development cohort (n = 321,703), then evaluated it in a held-out All of Us validation cohort (n = 80,423) and in the Genomic Health Initiative (n = 17,545). Compared with the remaining 90%, the top stPRS-CRC decile was associated with colorectal cancer with odds ratios of 1.94, 2.08 and 2.08 across the three cohorts, comparable to the best individual PRS (PGS003852). Individual-level concordance in high-risk classification, measured by the mean Jaccard index, was higher with stPRS-CRC than with PGS003852 (0.29 vs 0.20, 0.43 vs 0.25 and 0.27 vs 0.19; p < 0.001).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The work tackles a real barrier to return of results: two PRS that perform equally at population level can classify the same patient differently. The gain lies in classification consistency, not discrimination, and an odds ratio of about 2 for the top decile remains modest compared with monogenic syndromes; it is also a non-peer-reviewed preprint. A polygenic score does not replace the search for a germline variant in a patient with a suggestive personal or family history.

Analysis by Dr Thibaut Benquey