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

Bi-allelic inactivation of MSH3 or MLH3 (germline variant plus a somatic second hit) driving hypermutation with excess deletions and signature ID4, without microsatellite instability.

MSH3 and MLH3 are non-canonical DNA mismatch repair genes involved in repairing insertion-deletion mutations. The authors studied nearly 12,000 colorectal cancer (CRC) or multiple polyp cases and 460,000 controls, with cancer genome sequencing in 2,023 patients. One case carried bi-allelic MSH3 mutations and another bi-allelic MLH3 mutations; germline heterozygotes had an increased CRC risk (2.2-fold for MSH3, P = 6.6 × 10⁻⁵; 1.6-fold for MLH3, P = 0.028), through somatic second hits inactivating the wild-type allele — a single hit sometimes inactivating both MSH3 and the nearby APC gene. All MSH3- or MLH3-deficient CRCs were microsatellite-stable but hypermutant, with an approximately 12-fold excess of deletions of two or more base pairs and signature ID4 usually present (P < 0.0001), whereas tumours from heterozygotes without a second hit showed no hypermutation. The authors liken this phenotype to PMS2-related Lynch syndrome.

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

The model described is that of a classical tumour suppressor with incomplete penetrance, phenotypically close to PMS2-related Lynch syndrome: this raises the question of tailored genetic counselling and colonoscopic surveillance for MSH3 heterozygotes, while explaining why these tumours escape microsatellite instability screening. The key caveat is the preprint status and the authors' explicit warning that these findings should not guide practice as they stand. The modest relative risks (1.6 to 2.2) place these genes among low-to-moderate penetrance predispositions in any case, not to be managed like canonical Lynch syndrome.

Analysis by Dr Thibaut Benquey