Medulloblastomas with ELP1 pathogenic variants: A weakly penetrant syndrome with a restricted spectrum in a limited age window

Author:

Guerrini-Rousseau Léa12ORCID,Masliah-Planchon Julien3,Filser Mathilde3,Tauziède-Espariat Arnault4,Entz-Werle Natacha5,Maugard Christine M6,Hopman Saskia M J7,Torrejon Jacob89,Gauthier-Villars Marion10,Simaga Fatoumata10,Blauwblomme Thomas11ORCID,Beccaria Kevin11ORCID,Rouleau Etienne12ORCID,Dimaria Marina2,Grill Jacques12ORCID,Abbou Samuel213,Claret Béatrice14,Brugières Laurence2,Doz François1516ORCID,Bouchoucha Yassine16,Faure-Conter Cécile17,Bonadona Valerie18,Mansuy Ludovic19,de Carli Emilie20,Ingster Olivier21,Legrand Clémentine22,Pagnier Anne23,Berthet Pascaline24,Bodet Damien25,Julia Sophie26,Bertozzi Anne-Isabelle27,Wilems Marjolaine28,Maurage Claude-Alain29,Delattre Olivier30,Ayrault Olivier89,Dufour Christelle12ORCID,Bourdeaut Franck151630ORCID

Affiliation:

1. Molecular Predictors and New Targets in Oncology, Inserm U981 Team “Genomics and Oncogenesis of Pediatric Brain Tumors,” Gustave Roussy, Université Paris-Saclay , Villejuif , France

2. Department of Children and Adolescents Oncology, Gustave Roussy, Université Paris-Saclay , Villejuif , France

3. Department of Pathology and Diagnostic, Prognostic and Theranostic Medicine, Somatic Genetic Unit, Institut Curie, Paris Sciences Lettres Research University , Paris , France

4. Department of Neuropathology, Sainte Anne Hospital , Paris , France

5. Pediatric Hematology and Oncology Department, Strasbourg University Hospital, University of Strasbourg , Strasbourg , France

6. Department of Clinical Genetics, Strasbourg University Hospital , Strasbourg , France

7. Department of Genetics, University Medical Center Utrecht , Utrecht , the Netherlands

8. Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021 , Orsay , France

9. Institut Curie, Paris Sciences Lettres Research University, CNRS UMR, INSERM , Orsay , France

10. Department of Genetics, Institut Curie, Paris Sciences Lettres Research University , Paris , France

11. Necker-Enfants Malades University Hospital, Department of Pediatric Neurosurgery, Paris-Cité University , Paris , France

12. Cancer Genetics Unit, Department of Biology and Pathology, Institut Gustave Roussy , Villejuif , France

13. National Institute for Health and Medical Research (INSERM) U1015, Gustave Roussy , Villejuif , France

14. Psycho-Oncology Unit, Interdisciplinary Department of Supportive Care, Gustave Roussy, Université Paris-Saclay , Villejuif , France

15. Université Paris Cité , SIREDO Pediatric Cancer Center, Institut Curie, Paris , France

16. SIREDO Center (Care, Innovation Research in Pediatric, Adolescent and Young Adult Oncology), Institut Curie , Paris , France

17. Pediatric Hematology and Oncology Institut, Centre Léon Berard , Lyon , France

18. Clinical Oncogenetics Unit, Department of Prevention and Public Health, Centre Léon Bérard , Lyon , France

19. Department of Pediatric Hematology and Oncology, Centre Hospitalo-Universitaire de Nancy , Vandœuvre-lès-Nancy , France

20. Pediatric Hematology and Oncology Department, Angers University Hospital , Nancy , France

21. Department of Genetics, Angers University Hospital , Angers , France

22. Department of Genetics, Grenoble University Hospital , Grenoble , France

23. Department of Pediatric Hematology and Oncology, Centre Hospitalo-Universitaire de Grenoble , Grenoble , France

24. Department of Genetics, Centre François Baclesse , Caen , France

25. Pediatric Hematology and Oncology Department, Caen University Hospital , Caen , France

26. Department of Genetics, Toulouse University Hospital , Toulouse , France

27. Pediatric Hematology and Oncology Department, Toulouse University Hospital , Toulouse , France

28. Department of Medical Genetics, Montpellier University Hospital, Institute for Neurosciences of Montpellier, Univ Montpellier, INSERM , Montpellier , France

29. Laboratory of Neuropathology, Centre Oscar Lambret , Lille , France

30. INSERM U830, Cancer, Heterogeneity, Instability and Plasticity Laboratory Institut Curie , Paris , France

Abstract

Abstract Background ELP1 pathogenic variants (PV) have been recently identified as the most frequent variants predisposing to Sonic Hedgehog (SHH) medulloblastomas (MB); however, guidelines are still lacking for genetic counseling in this new syndrome. Methods We retrospectively reviewed clinical and genetic data of a French series of 29 ELP1-mutated MB. Results All patients developed SHH-MB, with a biallelic inactivation of PTCH1 found in 24 tumors. Other recurrent alterations encompassed the TP53 pathway and activation of MYCN/MYCL signaling. The median age at diagnosis was 7.3 years (range: 3–14). ELP1-mutated MB behave as sporadic cases, with similar distribution within clinical and molecular risk groups and similar outcomes (5 y – OS = 86%); no unusual side effect of treatments was noticed. Remarkably, a germline ELP1 PV was identified in all patients with available constitutional DNA (n = 26); moreover, all tested familial trio (n = 11) revealed that the PVs were inherited. Two of the 26 index cases from the French series had a family history of MB; pedigrees from these patients and from 1 additional Dutch family suggested a weak penetrance. Apart from MB, no cancer was associated with ELP1 PVs; second tumors reported in 4 patients occurred within the irradiation fields, in the usual time-lapse for expected radiotherapy-induced neoplasms. Conclusions The low penetrance, the “at risk’ age window limited to childhood and the narrow tumor spectrum, question the actual benefit of genetic screening in these patients and their family. Our results suggest restricting ELP1 germline sequencing to patients with SHH-MB, depending on the parents” request.

Funder

Foundation Gustave Roussy

INCa PRTK-19-027

St Baldrick’s Foundation

ADAM and Gustave Roussy

Publisher

Oxford University Press (OUP)

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