Article (Scientific journals)
Constitutional mismatch repair deficiency mimicking Lynch syndrome is associated with hypomorphic mismatch repair gene variants.
Gallon, Richard; Brekelmans, Carlijn; Martin, Marie et al.
2024In npj Precision Oncology, 8 (1), p. 119
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Abstract :
[en] 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.
Disciplines :
Laboratory medicine & medical technology
Author, co-author :
Gallon, Richard ;  Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. richard.gallon@newcastle.ac.uk
Brekelmans, Carlijn;  Centre for Human Genetics, University Hospital Leuven, Leuven, Belgium
Martin, Marie ;  Université de Liège - ULiège > Département des sciences cliniques
Bours, Vincent ;  Université de Liège - ULiège > GIGA > GIGA Cancer - Human Genetics
Schamschula, Esther ;  Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
Amberger, Albert;  Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
Muleris, Martine;  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, Chrystelle;  Département de Génétique, Institut Curie, Paris, France ; INSERM U830, Université de Paris, Paris, France
Dekervel, Jeroen;  Department of Digestive Oncology, University Hospital Leuven, Leuven, Belgium
De Hertogh, Gert;  Department of Pathology, University Hospital Leuven, Leuven, Belgium
COUPIER, Jérôme  ;  Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique
Colleye, Orphal ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Sépulchre, Edith  ;  Université de Liège - ULiège > GIGA
Burn, John ;  Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
Brems, Hilde ;  Centre for Human Genetics, University Hospital Leuven, Leuven, Belgium
Legius, Eric;  Centre for Human Genetics, University Hospital Leuven, Leuven, Belgium
Wimmer, Katharina ;  Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria. katharina.wimmer@i-med.ac.at
More authors (7 more) Less
Language :
English
Title :
Constitutional mismatch repair deficiency mimicking Lynch syndrome is associated with hypomorphic mismatch repair gene variants.
Publication date :
24 May 2024
Journal title :
npj Precision Oncology
eISSN :
2397-768X
Publisher :
Springer Science and Business Media LLC, England
Volume :
8
Issue :
1
Pages :
119
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
CRUK - Cancer Research UK
Available on ORBi :
since 03 June 2024

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