Comparison between germline and somatic loss-of-function RNF43 mutations reveals different genotype-phenotype associations and provides insights into the genetic mechanisms of colorectal tumourigenesis

Background: Germline RNF43 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 RNF43 variants in patients more representative of the general population and compared these with somatic RNF43 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 RNF43 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 RNF43 mutations, cases often lacked multiple polyps or a notable family history. Sometimes, CRCs developed independently of the germline RNF43 mutation. In case-control analyses, germline RNF43 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 ZNRF3 and a new driver, SFRP4.

Conclusion: RNF43 is a CRC predisposition gene, but risks are moderate, the reported polyposis phenotype is often absent and molecular phenocopies can occur. N-terminal germline RNF43 variants confer higher risk, although weak effects of C-terminal variants cannot be excluded. Genetic testing and patient management should incorporate these factors.