Background The MSH3 gene is part of the DNA mismatch repair system, but has never been shown to be involved in Lynch syndrome. A first report of four patients from two families, bearing biallelic MSH3 germline variants, with a phenotype of attenuated colorectal adenomatous polyposis raised the question of its involvement in hereditary cancer predisposition. The patients’ tumours exhibited elevated microsatellite alterations at selected tetranucleotide repeats (EMAST), a hallmark of MSH3 deficiency.
Methods We report five new unrelated patients with MSH3-associated polyposis. We describe their personal and familial history and study the EMAST phenotype in various normal and tumour samples, which are relevant findings based on the rarity of this polyposis subtype so far.
Results All patients had attenuated colorectal adenomatous polyposis, with duodenal polyposis in two cases. Both women had breast carcinomas. EMAST phenotype was present at various levels in different samples of the five patients, confirming the MSH3 deficiency, with a gradient of instability in polyps depending on their degree of dysplasia. The negative EMAST phenotype ruled out the diagnosis of germline MSH3 deficiency for two patients: one homozygous for a benign variant and one with a monoallelic large deletion.
Conclusion This report lends further credence to biallelic MSH3 germline pathogenic variants being involved in colorectal and duodenal adenomatous polyposis. Large-scale studies may help clarify the tumour spectrum and associated risks. Ascertainment of EMAST may help with the interpretation of variants of unknown significance. We recommend adding MSH3 to dedicated diagnostic gene panels.
- medical oncology
- genetic counseling
- genetic predisposition to disease
Data availability statement
Data sharing not applicable as no datasets generated and/or analysed for this study.
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Contributors Conceptualisation: M-CV and CC. Data curation: M-CV and CC. Formal Analysis: M-CV and JM-P. Investigation: AS and SV. Methodology: JM-P and LG. Project administration: DS-L, IB, JM-P and CC. Resources: CaC, MD, SF, AAO, RB, VC, MF and MBa. Software: SM, MBl, VS, KM and NH. Supervision: DS-L, IB and CC. Validation: JC and YA. Visualisation: M-CV, HD and BB. Writing—original draft: M-CV and CC. Writing—review and editing: all authors. All authors revised the manuscript critically and approved the version of the manuscript to be published. Guarantor: CC.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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