Constitutional mismatch repair deficiency mimicking Lynch syndrome is associated with hypomorphic mismatch repair gene variants.

Autor: Gallon R; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. richard.gallon@newcastle.ac.uk., Brekelmans C; Centre for Human Genetics, University Hospital Leuven, Leuven, Belgium., Martin M; CHU, University of Liège, Liège, Belgium., Bours V; CHU, University of Liège, Liège, Belgium., Schamschula E; Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria., Amberger A; Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria., Muleris M; Département de Génétique, AP-HP.Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.; Inserm UMRS_938, Sorbonne Université, Centre de Recherche Saint Antoine, Paris, France., Colas C; Département de Génétique, Institut Curie, Paris, France.; INSERM U830, Université de Paris, Paris, France., Dekervel J; Department of Digestive Oncology, University Hospital Leuven, Leuven, Belgium., De Hertogh G; Department of Pathology, University Hospital Leuven, Leuven, Belgium., Coupier J; Human Genetics, CHU Liège, Liège, Belgium., Colleye O; Department of Pathology, CHU Liège, Liège, Belgium., Sepulchre E; CHU, University of Liège, Liège, Belgium., Burn J; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Brems H; Centre for Human Genetics, University Hospital Leuven, Leuven, Belgium., Legius E; Centre for Human Genetics, University Hospital Leuven, Leuven, Belgium., Wimmer K; Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria. katharina.wimmer@i-med.ac.at.
Jazyk: angličtina
Zdroj: NPJ precision oncology [NPJ Precis Oncol] 2024 May 24; Vol. 8 (1), pp. 119. Date of Electronic Publication: 2024 May 24.
DOI: 10.1038/s41698-024-00603-z
Abstrakt: Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are distinct cancer syndromes caused, respectively, by mono- and bi-allelic germline mismatch repair (MMR) variants. LS predisposes to mainly gastrointestinal and genitourinary cancers in adulthood. CMMRD predisposes to brain, haematological, and LS-spectrum cancers from childhood. Two suspected LS patients with first cancer diagnosis aged 27 or 38 years were found to be homozygous for an MMR (likely) pathogenic variant, MSH6 c.3226C>T (p.(Arg1076Cys)), or variant of uncertain significance (VUS), MLH1 c.306G>A (p.(Glu102=)). MLH1 c.306G>A was shown to cause leaky exon 3 skipping. The apparent genotype-phenotype conflict was resolved by detection of constitutional microsatellite instability in both patients, a hallmark feature of CMMRD. A hypomorphic effect of these and other variants found in additional late onset CMMRD cases, identified by literature review, likely explains a LS-like phenotype. CMMRD testing in carriers of compound heterozygous or homozygous MMR VUS may find similar cases and novel hypomorphic variants. Individualised management of mono- and bi-allelic carriers of hypomorphic MMR variants is needed until we better characterise the associated phenotypes.
(© 2024. The Author(s).)
Databáze: MEDLINE
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