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Review
. 2024 Dec;32(12):1526-1541.
doi: 10.1038/s41431-024-01708-6. Epub 2024 Oct 17.

ERN GENTURIS guidelines on constitutional mismatch repair deficiency diagnosis, genetic counselling, surveillance, quality of life, and clinical management

Chrystelle Colas  1 , Léa Guerrini-Rousseau  2 , Manon Suerink  3 , Richard Gallon  4 , Christian P Kratz  5 , Éloïse Ayuso  6 ; ERN GENTURIS CMMRD Guideline Group; Laurence Brugières  2 , Katharina Wimmer  7
Collaborators, Affiliations
Review

ERN GENTURIS guidelines on constitutional mismatch repair deficiency diagnosis, genetic counselling, surveillance, quality of life, and clinical management

Chrystelle Colas et al. Eur J Hum Genet. 2024 Dec.

Abstract

Constitutional mismatch repair deficiency (CMMRD), first described 25 years ago, confers an extremely high and lifelong cancer risk, including haematologic, brain, and gastrointestinal tract malignancies, and is associated with several non-neoplastic features. Our understanding of this condition has improved and novel assays to assist CMMRD diagnosis have been developed. Surveillance protocols need adjustment taking into account recent observational prospective studies assessing their effectiveness. Response to immune checkpoint inhibitors and the effectiveness and toxicity of other treatments have been described. An update and merging of the different guidelines on diagnosis and clinical management of CMMRD into one comprehensive guideline was needed. Seventy-two expert members of the European Reference Network GENTURIS and/or the European care for CMMRD consortium and one patient representative developed recommendations for CMMRD diagnosis, genetic counselling, surveillance, quality of life, and clinical management based on a systematic literature search and comprehensive literature review and a modified Delphi process. Recommendations for the diagnosis of CMMRD provide testing criteria, propose strategies for CMMRD testing, and define CMMRD diagnostic criteria. Recommendations for surveillance cover each CMMRD-associated tumour type and contain information on starting age, frequency, and surveillance modality. Recommendations for clinical management cover cancer treatment, management of benign tumours or non-neoplastic features, and chemoprevention. Recommendations also address genetic counselling and quality of life. Based on existing guidelines and currently available data, we present 82 recommendations to improve and standardise the care of CMMRD patients in Europe. These recommendations are not meant to be prescriptive and may be adjusted based on individual decisions.

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Conflict of interest statement

Competing interests: All members of the ERN GENTURIS CMMRD Guideline Group, including the Core Working Group, have provided disclosure statements on all relationships that they have that might be perceived to be a potential conflict of interest. Amedeo Azizi reports receipt of honoraria or consultation fees from Alexion, AstraZeneca and Novartis. Kevin Beccaria reports previous employment with Carthera SAS. Laurence Brugières reports receipts of honoraria or consultation fees from ESAI and TAKEDA. Chrystelle Colas reports receipt of honoraria or consultation fees from AstraZeneca. Volodia Dangouloff-Ros reports receipt of grants/research support from GE Healthcare. Richard Gallon reports receipt of grants/research support from Cancer Research UK Catalyst and UK National Health Service. Christian Kratz reports support from BMBF ADDRess (01GM1909A) and Deutsche Kinderkrebsstiftung (DKS2021.25). Magali Svrcek reports receipt of grants/research support from Bayer and Roche, and receipt of honoraria or consultation fees from Astellas, MSD and Sanofi. All participants of the ERN GENTURIS CMMRD Delphi survey have provided disclosure statements on all relationships that they have that might be perceived to be a potential source of a competing interests. Andishe Attarbaschi reports receipt of honoraria or consultation fees from Amgen, Novartis, Jazz, Gilead and MSD. Patrick Benusiglio reports receipt of honoraria or consultation fees from AstraZeneca, BMS and MSD. Christof Kramm reports receipt of grants/research support from Deutsche Kinderkrebsstiftung (non-commercial), research collaboration with Bayer to develop NTRK-inhibitors, being a member of the advisory board for Boehringer Ingelheim, and participation in Blueprint Medicines ROVER trial NCT04773782. Eric Legius reports receipt of honoraria or consultation fees from Alexion and AstraZeneca. Rianne Oostenbrink reports receipt of grants/research support from EU Patient-centric clinical trial platform (EU-PEARL), which includes support from the European Union’s Horizon 2020 research and innovation program, EFPIA, Children’s Tumor Foundation, Global Alliance for TB Drug Development non-profit organization and Springworks Therapeutics Inc., receipt of honoraria or consultation fees from AstraZeneca, and participation in a speaker’s bureau sponsored by Alexion. Enrico Opocher reports receipt of honoraria or consultation fees from Alexion (RareDisease). Markus G. Seidel reports receipt of grants/research support from Takeda, Amgen and Novartis, and receipt of honoraria or consultation fees from Jazz, Amgen and Novartis.

Figures

Fig. 1
Fig. 1. Diagnostic decision tree.
Rectangles with rounded corners indicate clinical, genetic, and diagnostic status of the patient prior to and during diagnostic work-up (blue filling) as well as after diagnostic work-up (green, yellow and red filling). Diamonds with blue filling indicate decision points that can either be fulfilled (yes, follow the blue arrow) or not be fulfilled (no, follow the red arrow).
See this image and copyright information in PMC

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