Heterozygous germline mutations in MSH3, and probably MLH3, act as classical tumour suppressors, leading to excess somatic deletion mutations, signature ID4 and increased colorectal cancer risk.

MSH3

Loss of function of MSH3 or MLH3 through a somatic second hit inactivating the wild-type allele, producing deletion-driven hypermutation and signature ID4

MSH3 and MLH3 are non-canonical mismatch repair genes that correct insertion-deletion errors. The study analysed about 12,000 colorectal cancer or multiple polyp cases and 460,000 controls, with tumour genome sequencing in 2,023 patients. Germline heterozygotes had an increased colorectal cancer risk (2.2-fold for MSH3, p = 6.6 × 10⁻⁵; 1.6-fold for MLH3, p = 0.028), driven by somatic second hits inactivating the wild-type allele — a single hit sometimes inactivating both MSH3 and the neighbouring APC gene. All deficient tumours were microsatellite-stable yet hypermutant, with deletions of at least 2 bp increased around 12-fold and signature ID4 usually present (p < 0.0001); tumours from heterozygotes without a second hit showed no hypermutation. One case carried bi-allelic MSH3 variants and another bi-allelic MLH3 variants, with phenotypes resembling constitutional mismatch repair deficiency.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

MSH3 and MLH3 join the moderate-risk category: hazard ratios of 1.6 to 2.2 do not by themselves justify a dedicated surveillance protocol, and genetic counselling will for now remain risk information without a quantified management pathway. The strongest contribution is mechanistic: demonstrating the second hit and its link to signature ID4 provides a usable causality argument when facing a microsatellite-stable yet hypermutant colorectal cancer, which changes how a tumour profile is read more than it changes screening strategy. Both genes are already captured by exome and genome sequencing — the issue is their annotation and variant interpretation, not their addition to a targeted panel.

Analysis by Dr Thibaut Benquey