Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants

SIMPLE SUMMARY: A relevant proportion of colorectal cancer patients diagnosed at young age and/or with family history of that type of cancer do not carry germline mutations in know hereditary cancer genes. Moreover, studies aimed to identify additional high-risk colorectal cancer genes were either unsuccessful or identified genes that explain extremely few cases. We aimed to evaluate the role of the accumulation of colorectal cancer low-risk variants in familial and early-onset colorectal cancer patients. We observed that the accumulation of low-risk variants may explain a relevant number of these cases, particularly in the presence of family history of colorectal cancer and of the personal history of multiple colorectal cancers. If validated in other series of patients, the identification of familial/early-onset colorectal cancer patients with accumulation of low-risk variants will translate into personalized clinical management and to the identification of additional at-risk family members. ABSTRACT: A large proportion of familial and/or early-onset cancer patients do not carry pathogenic variants in known cancer predisposing genes. We aimed to assess the contribution of previously validated low-risk colorectal cancer (CRC) alleles to familial/early-onset CRC (fCRC) and to serrated polyposis. We estimated the association of CRC with a 92-variant-based weighted polygenic risk score (wPRS) using 417 fCRC patients, 80 serrated polyposis patients, 1077 hospital-based incident CRC patients, and 1642 controls. The mean wPRS was significantly higher in fCRC than in controls or sporadic CRC patients. fCRC patients in the highest (20th) wPRS quantile were at four-fold greater CRC risk than those in the middle quantile (10th). Compared to low-wPRS fCRC, a higher number of high-wPRS fCRC patients had developed multiple primary CRCs, had CRC family history, and were diagnosed at age ≥50. No association with wPRS was observed for serrated polyposis. In conclusion, a relevant proportion of mismatch repair (MMR)-proficient fCRC cases might be explained by the accumulation of low-risk CRC alleles. Validation in independent cohorts and development of predictive models that include polygenic risk score (PRS) data and other CRC predisposing factors will determine the implementation of PRS into genetic testing and counselling in familial and early-onset CRC.