Effect of a polygenic risk score in patients with late-onset, early-onset, familial, or hereditary colorectal cancer.

[OBJECTIVE] This study investigates how a polygenic risk score (PRS) influences colorectal cancer (CRC) risk across clinically and molecularly defined risk groups.

[METHODS] 1,839 European-descendant individuals were stratified according to low (<20%), intermediate (20 to 80%), or high (>80%) PRS, based on 93 CRC-associated SNPs, for four high risk groups: (i) Lynch syndrome [LS; with CRC: n = 679, CRC-free carriers: n = 422]; (ii) early-onset sporadic CRC [EOS-CRC; n = 518], (iii) positive family history for CRC [F-CRC; n = 220]; and, in EOS-CRC and F-CRC patients (iv) MSI/dMMR CRC [n = 144] vs MSS/pMMR CRC [n = 485]. CRC risk was compared to population-based controls [n = 3,119] and late-onset sporadic CRC patients from UK Biobank [LOS-CRC; n = 781] using multivariable logistic regression and Cox models.

[RESULTS] PRS was significantly increased in all risk groups compared to population controls. Being in the high PRS category doubled CRC risk in EOS-CRC and F-CRC corresponding to cumulative incidences before 50 and 75 years of 24% and 13%, respectively. PRS was significantly higher in EOS-CRC than LOS-CRC. In LS, PRS in non-CRC carriers lay between CRC-LS and population controls. Non-LS individuals with MSI/dMMR tumors showed significantly lower PRS than those with pMMR/MSS tumors, but no difference compared to LS CRC individuals.

[CONCLUSIONS] PRS most strongly influences CRC risk in unexplained EOS- and F-CRC. The effect in LS individuals strongly depends on the penetrance of the altered gene and study design. Non-significant trends can partly be explained by the sample size of subgroups. Larger collaborative, prospective studies are needed to validate PRS for personalized CRC risk stratification.