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

In total, 1839 European-descendant individuals were stratified according to low (<20%), intermediate (20% to 80%), or high (>80%) PRS, based on 93 CRC-associated single-nucleotide polymorphisms (SNPs), for 4 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 with population-based controls (n = 3119) and late-onset sporadic CRC patients from UK Biobank (LOS-CRC; n = 781) using multivariable logistic regression and Cox models.

RESULTS

Polygenic risk score (PRS) was significantly increased in all risk groups compared with 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. Polygenic risk score 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 with LS CRC individuals.

CONCLUSIONS

Polygenic risk score 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. Nonsignificant 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.