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

An integrated colorectal cancer PRS (stPRS-CRC) combining 28 published scores yields higher individual high-risk concordance, with odds ratios up to 2.08 across AoU and GHI.

• Why it matters: Published CRC PRS often agree on population-level association but assign different high-risk categories to the same people, complicating clinical genetic risk assessment and return of results.
• What they did: The authors built stPRS-CRC using PRSmix in the All of Us development cohort (n=321,703), then tested it in a held-out AoU validation cohort (n=80,423) and independently in GHI (n=17,545). They used logistic regression comparing the highest PRS decile versus the remaining 90% and quantified individual-level concordance with mean Jaccard indices.
• The result: stPRS-CRC maintained comparable CRC associations to the strongest single PRS (PGS003852) while improving concordance: mean Jaccard indices were 0.29 vs 0.20, 0.43 vs 0.25, and 0.27 vs 0.19 (all P<0.001). This suggests stPRS-CRC may support more consistent clinical frameworks for genetic risk assessment and RoR.

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