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 RNF43mutations 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.