Heterozygous germline mutations in <i>MSH3</i>, and probably <i>MLH3</i>, act as classical tumour suppressors, leading to excess somatic deletion mutations, signature ID4 and increased colorectal cancer risk.
case_control · Level III
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- Record sourced from PubMed, PMID 42728028.
- Also identified by DOI 10.1136/gutjnl-2026-338390.
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Abstract
<i>MSH3</i> and <i>MLH3</i> are non-canonical DNA mismatch repair genes, involved in repairing insertion-deletion mutations. Colorectal cancer (CRC) and adenomas have been reported in patients with bi-allelic germline <i>MSH3</i> mutations, and in a very few bi-allelic <i>MLH3</i> mutation carriers. We hypothesised that germline loss-of-function <i>MSH3</i> and <i>MLH3</i> mutations were akin to constitutional mismatch repair deficiency (cMMRd) and Lynch syndrome, such that CRC could result from either bi-allelic germline mutations or heterozygous germline mutations after second hits. About 12 000 CRC and multiple polyp cases and 460 000 controls were studied. 2023 patients underwent cancer genome sequencing. One CRC/multiple polyp case had bi-allelic <i>MSH3</i> mutations and another, bi-allelic <i>MLH3</i> mutations. <i>MSH3</i> and <i>MLH3</i> germline heterozygotes had an increased risk of CRC (2.2-fold, p<i>=</i>6.6×10<sup>-5</sup> and 1.6-fold, p<i>=</i>0.028, respectively), owing to somatic 'second hits' that inactivated the wildtype allele. Single second hits sometimes inactivated both <i>MSH3</i> and the nearby <i>APC</i> gene. All CRCs with <i>MSH3</i> or <i>MLH3</i> deficiency were microsatellite-stable but hypermutant. Deletions of ≥2 bp were particularly increased (~12-fold) and signature ID4 was usually present (p<i><</i>0.0001). CRCs from heterozygotes without 'second hits' showed no hypermutation. The phenotypes of bi-allelic <i>MSH3</i> and <i>MLH3</i> mutation carriers resemble some patients with cMMRd. Heterozygous germline <i>MSH3</i> and <i>MLH3</i> alleles have incomplete penetrance, but increase CRC risk via hypermutation, phenotypically resembling <i>PMS2-</i>mutant Lynch syndrome. A causal association with specific mutations has not previously been reported for ID4 in human tumours. ID4 probably does not have a single aetiology, but can result from <i>MSH3</i> or <i>MLH3</i> deficiency.