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<i>MSH3</i>: a confirmed predisposing gene for adenomatous polyposis

<i>MSH3</i>: a confirmed predisposing gene for adenomatous polyposis

1 déc. 2023Journal of Medical Genetics

DOI : 10.1136/jmg-2023-109341

Auteurs

Marie-Charlotte Villy, Julien Masliah-Planchon, Anne Schnitzler, Hélène Delhomelle, Bruno Buecher, Mathilde Filser, Kevin Merchadou, Lisa Golmard, Samia Melaabi, Sophie Vacher, Maud Blanluet, Voreak Suybeng, Carole Corsini, Marion Dhooge, Nadim Hamzaoui, Solenne Farelly, Amal Ait Omar, Robert Benamouzig, Vincent Caumette, Michel Bahuau, Joël Cucherousset, Yves Allory, Dominique Stoppa-Lyonnet, Ivan Bieche, Chrystelle Colas

Résumé

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.