Comparison between germline and somatic loss-of-function mutations reveals different genotype-phenotype associations and provides insights into the genetic mechanisms of colorectal tumourigenesis.

[BACKGROUND] Germline mutations cause a dominantly inherited syndrome of colorectal cancer (CRC) and serrated polyps. However, these data originate from highly selected families.

[OBJECTIVE] We assessed germline variants in patients more representative of the general population and compared these with somatic mutations in CRCs.

[DESIGN] We studied 49 823 CRC and/or polyp cases from the CORGI study, 100 000 Genomes (100kGP) and UK Biobank (UKB), alongside 165 250 controls. Somatic mutations were analysed in 2722 CRCs.

[RESULTS] Consistent with the literature, a germline loss-of-function variant (p.Thr158ProfsTer6) was found in a multigenerational CORGI family with early-onset CRC and serrated and/or filiform polyps. However, while 23 CRC/polyp cases and 47 controls from 100kGP or UKB had germline mutations, cases often lacked multiple polyps or a notable family history. Sometimes, CRCs developed independently of the germline mutation. In case-control analyses, germline variants were associated with CRC risk (OR=2.696, p=0.010), but penetrance was much greater for germline mutations in the N-terminal half of the gene. Germline C-terminal mutations conferred no increased CRC risk. However, somatic C-terminal mutations were pathogenic, perhaps because their relatively weak effects are supplemented by accompanying mutations in Wnt genes, including and a new driver, .

[CONCLUSION] is a CRC predisposition gene, but risks are moderate, the reported polyposis phenotype is often absent and molecular phenocopies can occur. N-terminal germline variants confer higher risk, although weak effects of C-terminal variants cannot be excluded. Genetic testing and patient management should incorporate these factors.