Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study


Ayse Bahar Ercan, Arthur and Sonia Labatt Brain Tumour Research Centre
Melyssa Aronson, Sinai Health
Nicholas R. Fernandez, Arthur and Sonia Labatt Brain Tumour Research Centre
Yuan Chang, Arthur and Sonia Labatt Brain Tumour Research Centre
Adrian Levine, The Hospital for Sick Children
Zhihui Amy Liu, Princess Margaret Cancer Centre
Logine Negm, Arthur and Sonia Labatt Brain Tumour Research Centre
Melissa Edwards, Arthur and Sonia Labatt Brain Tumour Research Centre
Vanessa Bianchi, Arthur and Sonia Labatt Brain Tumour Research Centre
Lucie Stengs, Arthur and Sonia Labatt Brain Tumour Research Centre
Jiil Chung, Arthur and Sonia Labatt Brain Tumour Research Centre
Abeer Al-Battashi, Royal Hospital
Agnes Reschke, Stanford Medicine
Alex Lion, Indiana University School of Medicine
Alia Ahmad, Children's Hospital Lahore
Alvaro Lassaletta, Hospital Infantil Universitario Niño Jesús
Alyssa T. Reddy, University of California, San Francisco
Amir F. Al-Darraji, University of Baghdad
Amish C. Shah, The Children's Hospital of Philadelphia
An Van Damme, Cliniques Universitaires Saint-Luc
Anne Bendel, Children's Minnesota
Aqeela Rashid, Shaukat Khanum Memorial Cancer Hospital and Research Centre
Ashley S. Margol, Keck School of Medicine of USC
Bethany L. Kelly, CHI-Saint Joseph Health Cancer Care
Bojana Pencheva, Children's Healthcare of Atlanta
Brandie Heald, Cleveland Clinic Foundation
Brianna Lemieux-Anglin, Centre Universitaire de Santé McGill
Bruce Crooks, IWK Health
Carl Koschmann, University of Michigan Medical School
Catherine Gilpin, Children's Hospital of Eastern Ontario, Ottawa
Christopher C. Porter, Children's Healthcare of Atlanta
David Gass, Atrium Health
David Samuel, Valley Children's Hospital

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The Lancet Oncology


Background: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. Methods: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. Findings: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9–12·6), and median follow-up from diagnosis was 7·2 years (3·6–14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80–99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8–3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30–52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55–82]), gastrointestinal cancers (89% [81–97]), and other solid tumours (96% [88–100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55–73] for PMS2, 49% [35–68] for MSH6, 19% [6–66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. Interpretation: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. Funding: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

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