Abstract
Simple SummaryA 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.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.
Highlights
Genetic predisposition to colorectal cancer (CRC) may be caused by germline pathogenic variants in high penetrance genes
WPRS was more strongly associated with familial/early-onset CRC (fCRC) when compared to controls (OR = 1.12; 95% confidence interval (CI): 1.09–1.14; p < 0.0001) and to sporadic CRC patients (OR = 1.03; 95% CI: 1.01–1.05; p = 0.014) (Table 2)
Our results suggest that a relevant proportion of mismatch repair (MMR)-proficient familial/early-onset
Summary
Genetic predisposition to colorectal cancer (CRC) may be caused by germline pathogenic variants in high penetrance genes. Germline pathogenic variants in APC and in the exonuclease domain of polymerases ε (POLE) and δ (POLD1) cause autosomal dominant adenomatous polyposis, increased risk to CRC, and to other cancers in the case of the polymerase proofreading-associated syndrome. Biallelic pathogenic variants in MUTYH, NTHL1, MSH3, and MLH3 cause recessive cancer syndromes characterized by adenomatous polyposis and increased risk to CRC. A large proportion of CRC families, mostly with nonpolyposis CRC and SP phenotypes, do not harbor pathogenic variants in known cancer-predisposing genes. Their clinical management is conducted based on their family history. Important efforts have been made to identify new high or moderate penetrance genes that explain the familial aggregation, early ages of onset, or polyposis phenotypes observed in those families or individuals, but the success achieved has been minimal [3,4,5]
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