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Acquired somatic MMR deficiency is a major cause of MSI tumor in patients suspected for “Lynch-like syndrome” including young patients

European Journal of Human Genetics volume 29, pages 482–488 (2021)Cite this article

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Abstract

Patients with tumors displaying high microsatellite instability (MSI-H) but no germline MMR inactivation are suspected for Lynch-like syndrome (LLS). To explore the involvement of acquired somatic MMR alteration as a cause, we screened 113 patient tumor samples for MMR gene variations and loss of heterozygosity. Somatic MMR alterations were found in 85.8% of patients including “double hits” in 63.7% of patients, mainly diagnosed with colon and endometrial cancers. Interestingly, 37.5% of them were under the age of 50, and seven patients were under 30. Somatic alterations were mainly attributed to the MLH1, MSH2 genes, likely reflecting the functional importance of these key MMR genes. Pathogenic variants co-existed in other cancer genes in particular the APC gene displaying a characteristic MMR deficiency-related “mutational signature”, indicating that it may be inactivated owing to MMR deficiency. We speculated that APC inactivation could trigger an accelerated malignant transformation underlying early-onset cancers. Our findings provide further insight into the mechanisms underlying LLS, somatic MMR inactivation being a major cause for early-onset LLS through pathways differing from those involved in late-onset sporadic cases.

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Acknowledgements

We thank Drs. E. Barouk-Simonet, B. Buecher, MN. Bonnet-Dupeyron, O. Caron, C. Corsini, F. Desseigne, M. Dhooge, S. Fert Ferrer, S. Giraud, M. Lebrun, D. Leroux, JM. Limacher, A. Lortholary, D. Malka, T. Martin-Denavit, S. Olschwang, F. Prieur, JC. Saurin, and their genetic counseling assistants for case collection and for providing clinical information. We thank Drs. O. Cabaret, C. Ferraro-Peyret, L. Golmard, C. Maugard for tumor sampling and DNA preparation. And we thank Mrs. Brigitte Manship for manuscript editing assistance.

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Authors and Affiliations

  1. Centre Léon Bérard, Laboratory of constitutional genetics for frequent cancer HCL-CLB, 69008, Lyon, France

    Cedrick Lefol, Pierre Naïbo, Eric Ruano, Chloé Grand-Masson & Qing Wang

  2. Centre Léon Bérard, Gilles-Thomas bioinformatics platform, 69008, Lyon, France

    Emilie Sohier, Christian Baudet & Alain Viari

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  1. Cedrick Lefol
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  2. Emilie Sohier
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Correspondence to Qing Wang.

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Lefol, C., Sohier, E., Baudet, C. et al. Acquired somatic MMR deficiency is a major cause of MSI tumor in patients suspected for “Lynch-like syndrome” including young patients. Eur J Hum Genet 29, 482–488 (2021). https://doi.org/10.1038/s41431-020-00778-6

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