N Lavoine1, C Colas2, M Muleris3, S Bodo3, A Duval3, N Entz-Werle4, F Coulet5, O Cabaret6, F Andreiuolo7, C Charpy8, G Sebille9, Q Wang10, S Lejeune11, M P Buisine12, D Leroux13, G Couillault14, G Leverger15, J P Fricker16, R Guimbaud17, M Mathieu-Dramard18, G Jedraszak18, O Cohen-Hagenauer19, L Guerrini-Rousseau1, F Bourdeaut20, J Grill21, O Caron22, S Baert-Dusermont23, J Tinat23, G Bougeard23, T Frébourg23, L Brugières1. 1. Department of Children and Adolescents Oncology, Gustave Roussy Cancer Campus, Villejuif, France. 2. Laboratory of Oncogenetics and Angiogenetics, Genetics Department, Pitié-Salpêtrière University Hospital, APHP, Paris, France INSERM, UMR_S 938, CDR Saint-Antoine, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France. 3. INSERM, UMR_S 938, CDR Saint-Antoine, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France. 4. Department of Pediatric Oncology, Strasbourg University Hospital, Strasbourg, France. 5. Laboratory of Oncogenetics and Angiogenetics, Genetics Department, Pitié-Salpêtrière University Hospital, APHP, Paris, France. 6. Department of Biology and Medical Pathology, Unit of Genetics, Gustave Roussy Cancer Campus, Villejuif, France. 7. Department of Neuropathology, Sainte-Anne Hospital, APHP, Paris, France. 8. Department of Pathology, Gustave Roussy Cancer Institute, Villejuif, France. 9. Department of Dermatology, Gustave Roussy Cancer Institute, Villejuif, France. 10. Plateforme mixte de génétique constitutionnelle des cancers fréquents HCL-CLB, Centre Léon Bérard, Lyon, France. 11. Unit of Molecular Oncology and Genetics, Institute of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France. 12. Unit of Molecular Oncology and Genetics, Institute of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France Inserm UMR837, Lille, France North of France University, Lille, France. 13. Department of Genetics, Grenoble University Hospital, Grenoble, France. 14. Département of Pediatrics, Dijon University Hospital, Dijon, France. 15. Paediatric Onco-Haematology Unit, APHP, Armand Trousseau Hospital, UPMC Univ Paris 06, France. 16. Department of Oncogenetics, Centre Paul Strauss, Strasbourg, France. 17. Department of Digestive Oncology, Claudius Régaud Institute and Toulouse University Hospital, Toulouse, France. 18. Unit of Medical Genetics, Amiens University Hospital, Amiens, France. 19. Department of Oncogenetics, Saint-Louis University Hospital, APHP, Paris, France. 20. Department of Pediatric Oncology, Curie Institute, Paris, France. 21. Department of Children and Adolescents Oncology, Gustave Roussy Cancer Campus, Villejuif, France CNRS UMR 8203 "Vectorology & Anticancer Treatments," Gustave Roussy & Paris-Sud University, Villejuif, France. 22. Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France. 23. Laboratory of Genetics, Rouen University Hospital, Rouen, France.
Abstract
BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a childhood cancer predisposition syndrome involving biallelic germline mutations of MMR genes, poorly recognised by clinicians so far. METHODS: Retrospective review of all 31 patients with CMMRD diagnosed in French genetics laboratories in order to describe the characteristics, treatment and outcome of the malignancies and biological diagnostic data. RESULTS: 67 tumours were diagnosed in 31 patients, 25 (37%) Lynch syndrome-associated malignancies, 22 (33%) brain tumours, 17 (25%) haematological malignancies and 3 (5%) sarcomas. The median age of onset of the first tumour was 6.9 years (1.2-33.5). Overall, 22 patients died, 9 (41%) due to the primary tumour. Median survival after the diagnosis of the primary tumour was 27 months (0.26-213.2). Failure rate seemed to be higher than expected especially for T-cell non-Hodgkin's lymphoma (progression/relapse in 6/12 patients). A familial history of Lynch syndrome was identified in 6/23 families, and consanguinity in 9/23 families. PMS2 mutations (n=18) were more frequent than other mutations (MSH6 (n=6), MLH1 (n=4) and MSH2 (n=3)). CONCLUSIONS: In conclusion, this unselected series of patients confirms the extreme severity of this syndrome with a high mortality rate mostly related to multiple childhood cancers, and highlights the need for its early detection in order to adapt treatment and surveillance. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a childhood cancer predisposition syndrome involving biallelic germline mutations of MMR genes, poorly recognised by clinicians so far. METHODS: Retrospective review of all 31 patients with CMMRD diagnosed in French genetics laboratories in order to describe the characteristics, treatment and outcome of the malignancies and biological diagnostic data. RESULTS: 67 tumours were diagnosed in 31 patients, 25 (37%) Lynch syndrome-associated malignancies, 22 (33%) brain tumours, 17 (25%) haematological malignancies and 3 (5%) sarcomas. The median age of onset of the first tumour was 6.9 years (1.2-33.5). Overall, 22 patientsdied, 9 (41%) due to the primary tumour. Median survival after the diagnosis of the primary tumour was 27 months (0.26-213.2). Failure rate seemed to be higher than expected especially for T-cell non-Hodgkin's lymphoma (progression/relapse in 6/12 patients). A familial history of Lynch syndrome was identified in 6/23 families, and consanguinity in 9/23 families. PMS2 mutations (n=18) were more frequent than other mutations (MSH6 (n=6), MLH1 (n=4) and MSH2 (n=3)). CONCLUSIONS: In conclusion, this unselected series of patients confirms the extreme severity of this syndrome with a high mortality rate mostly related to multiple childhood cancers, and highlights the need for its early detection in order to adapt treatment and surveillance. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Entities:
Keywords:
CMMRD; MMR; childhood cancer; genetic predisposition; multiple cancer
Authors: Ronja Adam; Isabel Spier; Bixiao Zhao; Michael Kloth; Jonathan Marquez; Inga Hinrichsen; Jutta Kirfel; Aylar Tafazzoli; Sukanya Horpaopan; Siegfried Uhlhaas; Dietlinde Stienen; Nicolaus Friedrichs; Janine Altmüller; Andreas Laner; Stefanie Holzapfel; Sophia Peters; Katrin Kayser; Holger Thiele; Elke Holinski-Feder; Giancarlo Marra; Glen Kristiansen; Markus M Nöthen; Reinhard Büttner; Gabriela Möslein; Regina C Betz; Angela Brieger; Richard P Lifton; Stefan Aretz Journal: Am J Hum Genet Date: 2016-07-28 Impact factor: 11.025
Authors: Verena Sailer; Kenneth Wa Eng; Tuo Zhang; Rohan Bareja; David J Pisapia; Alexandros Sigaras; Bhavneet Bhinder; Alessandro Romanel; David Wilkes; Evan Sticca; Joanna Cyrta; Rema Rao; Sheena Sahota; Chantal Pauli; Shaham Beg; Samaneh Motanagh; Myriam Kossai; Jacqueline Fontunge; Loredana Puca; Hanna Rennert; Jenny Zhaoying Xiang; Noah Greco; Rob Kim; Theresa Y MacDonald; Terra McNary; Mirjam Blattner-Johnson; Marc H Schiffman; Bishoy M Faltas; Jeffrey P Greenfield; David Rickman; Eleni Andreopoulou; Kevin Holcomb; Linda T Vahdat; Douglas S Scherr; Koen van Besien; Christopher E Barbieri; Brian D Robinson; Howard Alan Fine; Allyson J Ocean; Ana Molina; Manish A Shah; David M Nanus; Qiulu Pan; Francesca Demichelis; Scott T Tagawa; Wei Song; Juan Miguel Mosquera; Andrea Sboner; Mark A Rubin; Olivier Elemento; Himisha Beltran Journal: JCO Precis Oncol Date: 2019-09-20
Authors: Thomas B Alexander; Rose B McGee; Erica C Kaye; Mary Beth McCarville; John K Choi; Cary P Cavender; Kim E Nichols; John T Sandlund Journal: Pediatr Blood Cancer Date: 2016-04-01 Impact factor: 3.167
Authors: Andishe Attarbaschi; Elisa Carraro; Oussama Abla; Shlomit Barzilai-Birenboim; Simon Bomken; Laurence Brugieres; Eva Bubanska; Birgit Burkhardt; Alan K S Chiang; Monika Csoka; Alina Fedorova; Janez Jazbec; Edita Kabickova; Zdenka Krenova; Jelena Lazic; Jan Loeffen; Georg Mann; Felix Niggli; Natalia Miakova; Tomoo Osumi; Leila Ronceray; Anne Uyttebroeck; Denise Williams; Wilhelm Woessmann; Grazyna Wrobel; Marta Pillon Journal: Haematologica Date: 2016-08-11 Impact factor: 9.941
Authors: Dita Gratzinger; Elaine S Jaffe; Amy Chadburn; John K C Chan; Daphne de Jong; John R Goodlad; Jonathan Said; Yasodha Natkunam Journal: Am J Clin Pathol Date: 2017-02-01 Impact factor: 2.493