Constitutional mismatch repair deficiency-associated brain tumors: report from the European C4CMMRD consortium

Léa Guerrini-Rousseau; Pascale Varlet; Chrystelle Colas; Felipe Andreiuolo; Franck Bourdeaut; Karin Dahan; Christine Devalck; Cécile Faure-Conter; Maurizio Genuardi; Yael Goldberg; Michaela Kuhlen; Salma Moalla; Enrico Opocher; Vanessa Perez-Alonso; Astrid Sehested; Irene Slavc; Sheila Unger; Katharina Wimmer; Jacques Grill; Laurence Brugières

doi:10.1093/noajnl/vdz033

Constitutional mismatch repair deficiency-associated brain tumors: report from the European C4CMMRD consortium

Neurooncol Adv. 2019 Dec 2;1(1):vdz033. doi: 10.1093/noajnl/vdz033. eCollection 2019 May-Dec.

Authors

Léa Guerrini-Rousseau^{1

2}, Pascale Varlet³, Chrystelle Colas⁴, Felipe Andreiuolo³, Franck Bourdeaut⁵, Karin Dahan⁶, Christine Devalck⁷, Cécile Faure-Conter⁸, Maurizio Genuardi^{9

10}, Yael Goldberg¹¹, Michaela Kuhlen¹², Salma Moalla¹³, Enrico Opocher¹⁴, Vanessa Perez-Alonso¹⁵, Astrid Sehested¹⁶, Irene Slavc¹⁷, Sheila Unger¹⁸, Katharina Wimmer¹⁹, Jacques Grill^{1

2}, Laurence Brugières¹

Affiliations

¹ Department of Pediatric and Adolescents Oncology, Gustave Roussy Cancer Center, Paris-Saclay University, Villejuif, France.
² Gustave Roussy Cancer Center, Unite Mixte de Recherche 8203, Centre National de la Recherche Scientifique, Paris-Saclay University, Villejuif, France.
³ Department of Neuropathology, Sainte Anne Hospital, Rene Descartes University, Paris, France.
⁴ Curie Institute, Genetic Department, Paris, France.
⁵ Curie Institute, SIREDO Cancer Center (Care, innovation and research in pediatric, adolescents and young adults oncology), Paris, France.
⁶ Hôpital Universitaire Reine Fabiola (HUDERF), Genetic department, Université Libre de Belgique (ULB), Brussels, Belgium.
⁷ Department of Hemato-Oncology, Hôpital Universitaire Reine Fabiola (HUDERF), Université Libre de Belgique (ULB). Brussels - Belgium.
⁸ Centre Leon Berard, Pediatric hemato-oncology institute (IHOPe), Lyon, France.
⁹ Fondazione Policlinico Universitario A. Gemelli IRCCS, UOC Genetica Medica, Rome, Italy.
¹⁰ Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore, Rome, Italy.
¹¹ Raphael Recanati Genetics Institute, Beilinson Hospital, Rabin Medical Center, Petach Tikva, Israel.
¹² Department of Pediatric Oncology, University Children´s Hospital, Hematology and Clinical Immunology Duesseldorf, Germany.
¹³ Department of Radiology, Gustave Roussy Cancer Center, Université Paris-Saclay, Villejuif, France.
¹⁴ Azienda Ospedaliera di Padova, Pediatric Oncology & Hematology, Padova, Italy.
¹⁵ Hospital Universitario Doce de Octubre, Unidad de Oncología Pediátrica, Madrid, Spain.
¹⁶ Copenhagen University Hospital, Department of pediatrics and adolescent medicin, Copenhagen, Denmark.
¹⁷ Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
¹⁸ Centre Hospitalier Universitaire Vaudois, Division of Genetic Medicine, University of Lausanne, Lausanne Switzerland.
¹⁹ Institute of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.

Abstract

Background: Malignant brain tumors (BT) are among the cancers most frequently associated with constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer predisposition syndrome resulting from biallelic germline mutations in mismatch repair genes. This study analyzed data from the European "Care for CMMRD" (C4CMMRD) database to describe their clinical characteristics, treatments, and outcome with the aim of improving its diagnosis/treatment.

Methods: Retrospective analysis of data on patients with CMMRD and malignant BT from the C4CMMRD database up to July 2017.

Results: Among the 87 registered patients, 49 developed 56 malignant BTs: 50 high-grade gliomas (HGG) (with giant multinucleated cells in 16/21 histologically reviewed tumors) and 6 embryonal tumors. The median age at first BT was 9.2 years [1.1-40.6], with nine patients older than 18. Twenty-seven patients developed multiple malignancies (including16 before the BT). Most patients received standard treatment, and eight patients immunotherapy for relapsed HGG. The 3- and 5-year overall survival (OS) rates were 30% (95% CI: 19-45) and 22% (95% CI: 12-37) after the first BT, with worse prognosis for HGG (3-year OS = 20.5%). Six patients were alive (median follow-up 2.5 years) and 43 dead (38 deaths, 88%, were BT-related). Other CMMRD-specific features were café-au-lait macules (40/41), multiple BTs (5/15), developmental brain anomalies (11/15), and consanguinity (20/38 families).

Conclusions: Several characteristics could help suspecting CMMRD in pediatric malignant BTs: giant cells on histology, previous malignancies, parental consanguinity, café-au-lait macules, multiple BTs, and developmental brain anomalies. The prognosis of CMMRD-associated BT treated with standard therapies is poor requiring new therapeutic up-front approaches.

Keywords: MMR biallelic germline mutation; brain tumor; café-au-lait spot; childhood cancer; constitutional mismatch repair deficiency; high-grade glioma; predisposition.