Background Constitutional mismatch repair deficiency syndrome (CMMRD) is the most aggressive cancer predisposition syndrome associated with multiorgan cancers, often presenting in childhood. There is variability in age and presentation of cancers and benign manifestations mimicking neurofibromatosis type 1. Genetic testing may not be informative and is complicated by pseudogenes associated with the most commonly associated gene, PMS2. To date, no diagnostic criteria exist. Since surveillance and immune-based therapies are available, establishing a CMMRD diagnosis is key to improve survival.
Methods In order to establish a robust diagnostic path, a multidisciplinary international working group, with representation from the two largest consortia (International Replication Repair Deficiency (IRRD) consortium and European Consortium Care for CMMRD (C4CMMRD)), was formed to establish diagnostic criteria based on expertise, literature review and consensus.
Results The working group established seven diagnostic criteria for the diagnosis of CMMRD, including four definitive criteria (strong evidence) and three likely diagnostic criteria (moderate evidence). All criteria warrant CMMRD surveillance. The criteria incorporate germline mismatch repair results, ancillary tests and clinical manifestation to determine a diagnosis. Hallmark cancers for CMMRD were defined by the working group after extensive literature review and consultation with the IRRD and C4CMMRD consortia.
Conclusions This position paper summarises the evidence and rationale to provide specific guidelines for CMMRD diagnosis, which necessitates appropriate surveillance and treatment.
- gastrointestinal diseases
- medical oncology
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Contributors All authors contributed to planning, conduct and reporting of this work.
Funding The International Replication Repair Deficiency (IRRD) consortium is partially supported by grants from Stand Up to Cancer (SU2C-AACR-CT07-17), Canadian Institutes of Health Research (CIHR) (#PJT-156006 and 108188-001 as part of Joint Canada-Israel Health Research Program) and Meagan’s Walk (MW-2014-10). The C4CMMRD database is supported by La Fondation Gustave Roussy, Guérir le cancer de l’Enfant au 21ème siècle. These agencies had no involvement in the study design, analysis or interpretation of data, writing or decision to submit for publication.
Competing interests HH reports the following financial relationships: Scientific Advisory Board at Invitae Genetics, Medical Advisory Board at Promega, Scientific Advisory Board at Genome Medical, and consultant at 23andMe. None of the relationships presents a conflict of interest in this study. KJ is a full-time employee at Ambry Genetics. This does not present a conflict of interest in this study. LB reports grants from Fondation Gustave Roussy, during the conduct of the study. UT reports grants from SU2C Catalyst, grants from Meagan’s Walk, grants from IDRC - Joint Canada-Israel Health Program and grants from Canadian Institutes of Health, during the conduct of the study.
Patient consent for publication Parental/guardian consent obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
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