BACKGROUND: Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare childhood cancer predisposition syndrome associated with a broad spectrum of malignancies, including non-Hodgkin lymphomas (NHL). Most patients die due to cancer before the age of 20 years. Limited data exist on CMMRD-associated lymphomas and their outcome. METHODS: We conducted a retrospective study including all CMMRD-associated NHL patients registered before 2020 in the European and North American databases or reported by members of the European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL). Events considered to define event-free survival included relapse/progression, second malignancy (SML), or death, whichever occurred first. FINDINGS: The analysis included 74 patients, with 20 having multiple metachronous NHL. The median age at diagnosis was 9.4 years. Previous malignancies were reported in 36% of the patients, café au lait spots in 96%, and consanguinity in 54%. The initial lymphoma subtypes were 53 T-cell lymphoblastic lymphomas (T-LBL), four B-lymphoblastic lymphomas, and 17 mature B-cell non-Hodgkin lymphoma (B-NHL). All patients were treated with curative intent, with current chemotherapy regimens adapted to their subtype. The median follow-up was 8.7 years. After the first lymphoma, the 5-year event-free and overall survival rates were, respectively, 23.5% [95% confidence interval (CI): 14.9-35.1] and 61.5% [95% CI: 49.6-72.1]. The 5-year cumulative risk of progression/relapse, SML or death as a first event was 20.8%, 52.9%, and 2.7%. INTERPRETATION: Standard treatments for sporadic NHL are effective in most CMMRD-associated NHL cases, but multiple malignancies, including lymphomas, impair prognosis. Future strategies should evaluate the potential of less genotoxic therapies, including immunotherapy, in preventing SMLs while maintaining effective control of NHL.

Biostatistics and Epidemiology Departement Gustave Roussy Oncostat U1018 INSERM labeled Ligue Contre le Cancer Paris Saclay University Villejuif France

Cancer Research UK Clinical Trials Unit Institute of Cancer and Genomic Sciences University of Birmingham Edgbaston Birmingham UK

Consortium for Biomedical Research in Cancer CIBERONC Carlos 3 Institute of Health Madrid Spain

Department of Children and Adolescents Oncology Gustave Roussy Cancer Paris Saclay University Villejuif France

Department of Genetics Institut Curie University Paris Sciences Lettres Paris France

Department of Oncology KU Leuven Pediatric Hemato Oncology University Hospitals Leuven Herestraat 49 Leuven Belgium

Department of Pediatric Hematology and Oncology Charles University and University Hospital Motol Prague Czech Republic

Department of Pediatric Hematology Oncology Schneider Children's Medical Center and Faculty of Medicine Tel Aviv University Tel Aviv Israel

Department of Pediatric Oncology Hematology and Transplantology Poznan University of Medical Sciences Poznan Poland

Division of Hematology and Oncology The Hospital for Sick Children Toronto Ontario Canada

Fundación Publica Galega de Medicina Xenómica SERGAS Grupo de Medicina Xenómica Universidad de Santiago de Compostela Instituto de Investigación Sanitaria de Santiago Santiago de Compostela Spain

Hemato Oncology Department HUB ULB HUDERF Brussels Belgium

Hereditary Cancer Genetic Diagnostic Laboratory University Hospital Doce de Octubre Madrid Spain

Hereditary Cancer Program Catalan Institute of Oncology Bellvitge Biomedical Research Institute ONCOBELL Program Barcelona Spain

Institute of Human Genetics Medical University of Innsbruck Innsbruck Austria

National Children's Research Centre at Children's Health Ireland Dublin Ireland

NHL BFM Study Center and Pediatric Hematology Oncology and BMT University Hospital Muenster Muenster Germany

Pediatric Hematology and Oncology Hannover Medical School Hannover Germany

Pediatric Oncology Unit University Hospital Doce de Octubre Madrid Spain

Princess Máxima Center for Pediatric Oncology 3584 CS Utrecht The Netherlands

Raphael Recanati Genetics Institute Rabin Medical Center Beilinson Hospital Petah Tikva Israel

Sackler School for Faculty Tel Aviv University Tel Aviv Israel

St Anna Children's Cancer Research Institute Vienna Austria

St Anna Children's Hospital Medical University Vienna Austria

The Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children Toronto Ontario Canada

Zobrazit více v PubMed

Wang Q, Lasset C, Desseigne F, et al. Neurofibromatosis and early onset of cancers in hMLH1‐deficient children. Cancer Res. 1999;59(2):294‑297.

Wimmer K, Kratz CP, Vasen HFA, et al. Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium ‘Care for CMMRD’ (C4CMMRD). J Med Genet. 2014;51(6):355‑365.

Aronson M, Colas C, Shuen A, et al. Diagnostic criteria for constitutional mismatch repair deficiency (CMMRD): recommendations from the international consensus working group. J Med Genet. 2022;59(4):318‑327.

Vasen HFA, Ghorbanoghli Z, Bourdeaut F, et al. Guidelines for surveillance of individuals with constitutional mismatch repair‐deficiency proposed by the European Consortium ‘Care for CMMR‐D’ (C4CMMR‐D). J Med Genet. 2014;51(5):283‑293.

Tabori U, Hansford JR, Achatz MI, et al. Clinical management and tumor surveillance recommendations of inherited mismatch repair deficiency in childhood. Clin Cancer Res. 2017;23(11):e32‑e37.

Lavoine N, Colas C, Muleris M, et al. Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort. J Med Genet. 2015;52(11):770‑778.

Bodo S, Colas C, Buhard O, et al. Diagnosis of constitutional mismatch repair‐deficiency syndrome based on microsatellite instability and lymphocyte tolerance to methylating agents. Gastroenterology. 2015;149(4):1017‐1029.e3.

Stojic L, Brun R, Jiricny J. Mismatch repair and DNA damage signalling. DNA Repair (Amst). 2004;3(8‑9):1091‑1101.

Karran P, Offman J, Bignami M. Human mismatch repair, drug‐induced DNA damage, and secondary cancer. Biochimie. 2003;85(11):1149‑1160.

Bignami M, Casorelli I, Karran P. Mismatch repair and response to DNA‐damaging antitumour therapies. Eur J Cancer. 2003;39(15):2142‑2149.

Suerink M, Wimmer K, Brugieres L, et al. Report of the fifth meeting of the European Consortium ‘Care for CMMRD’ (C4CMMRD), Leiden, the Netherlands, July 6th 2019. Fam Cancer. 2021;20(1):67‑73.

Beishuizen A, Mellgren K, Andrés M, et al. Improving outcomes of childhood and young adult non‐Hodgkin lymphoma: 25 years of research and collaboration within the framework of the European Intergroup for Childhood Non‐Hodgkin Lymphoma. Lancet Haematol. 2023;10(3):e213‑e224.

Suerink M, Ripperger T, Messiaen L, et al. Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy. J Med Genet. 2019;56(2):53‑62.

Attarbaschi A, Carraro E, Abla O, et al. Non‐Hodgkin lymphoma and pre‐existing conditions: spectrum, clinical characteristics and outcome in 213 children and adolescents. Haematologica. 2016;101(12):1581‑1591.

Ripperger T, Schlegelberger B. Acute lymphoblastic leukemia and lymphoma in the context of constitutional mismatch repair deficiency syndrome. Eur J Med Genet. 2016;59(3):133‑142.

Kroeze E, Weijers DD, Hagleitner MM, et al. High prevalence of constitutional mismatch repair deficiency in a pediatric T‐cell lymphoblastic lymphoma cohort. Hemasphere. 2022;6(1):e668.

Scott RH, Homfray T, Huxter NL, et al. Familial T‐cell non‐Hodgkin lymphoma caused by biallelic MSH2 mutations. J Med Genet. 2007;44(7):e83.

Kratz CP, Niemeyer CM, Jüttner E, et al. Childhood T‐cell non‐Hodgkin's lymphoma, colorectal carcinoma and brain tumor in association with café‐au‐lait spots caused by a novel homozygous PMS2 mutation. Leukemia. 2008;22(5):1078‑1080.

Ilenčíková D. [Constitutional mismatch repair‐deficiency syndrome (CMMR‐D)—a case report of a family with biallelic MSH6 mutation]. Klin Onkol. 2012;25 Suppl:S34‐S38.

Bougeard G, Olivier‐Faivre L, Baert‐Desurmont S, et al. Diversity of the clinical presentation of the MMR gene biallelic mutations. Fam Cancer. 2014;13(1):131‑135.

Nguyen A, Bougeard G, Koob M, et al. MSI detection and its pitfalls in CMMRD syndrome in a family with a bi‐allelic MLH1 mutation. Fam Cancer. 2016;15(4):571‑577.

Taeubner J, Wimmer K, Muleris M, et al. Diagnostic challenges in a child with early onset desmoplastic medulloblastoma and homozygous variants in MSH2 and MSH6. Eur J Hum Genet. 2018;26(3):440‑444.

Murphy SB. Classification, staging and end results of treatment of childhood non‐Hodgkin's lymphomas: dissimilarities from lymphomas in adults. Semin Oncol. 1980;7(3):332‑339.

Minard‐Colin V, Brugières L, Reiter A, et al. Non‐Hodgkin lymphoma in children and adolescents: progress through effective collaboration, current knowledge, and challenges ahead. J Clin Oncol. 2015;33(27):2963‑2974.

Landmann E, Burkhardt B, Zimmermann M, et al. Results and conclusions of the European Intergroup EURO‐LB02 trial in children and adolescents with lymphoblastic lymphoma. Haematologica. 2017;102(12):2086‑2096.

Gallon R, Mühlegger B, Wenzel SS, et al. A sensitive and scalable microsatellite instability assay to diagnose constitutional mismatch repair deficiency by sequencing of peripheral blood leukocytes. Hum Mutat. 2019;40(5):649‑655.

Burkhardt B, Hermiston ML. Lymphoblastic lymphoma in children and adolescents: review of current challenges and future opportunities. Br J Haematol. 2019;185(6):1158‑1170.

Mas‐Ponte D, McCullough M, Supek F. Spectrum of DNA mismatch repair failures viewed through the lens of cancer genomics and implications for therapy. Clin Sci (Lond). 2022;136(5):383‑404.

Das A, Sudhaman S, Morgenstern D, et al. Genomic predictors of response to PD‐1 inhibition in children with germline DNA replication repair deficiency. Nat Med. 2022;28(1):125‑135.

Heudel P, Chabaud S, Perol D, Ray‐Coquard I, Blay JY. Reduced risk of second primary cancer in patients treated with immune checkpoint inhibitors for a first cancer. Ann Oncol. 2020;31(12):1773‑1775.