Léa Guerrini-Rousseau1, Christelle Dufour1, Pascale Varlet2, Julien Masliah-Planchon3,4, Franck Bourdeaut3,5,6, Marine Guillaud-Bataille7, Rachid Abbas8,9, Anne-Isabelle Bertozzi10, Fanny Fouyssac11, Sophie Huybrechts12, Stéphanie Puget13, Brigitte Bressac-De Paillerets7, Olivier Caron3,4,14, Nicolas Sevenet15,16,17, Marina Dimaria14, Sophie Villebasse14, Olivier Delattre1, Dominique Valteau-Couanet1, Jacques Grill18, Laurence Brugières1. 1. Département de Cancérologie de l'Enfant et de l'Adolescent, Gustave Roussy, Université Paris-Saclay, Villejuif, France. 2. Service de neuropathologie, Hôpital Sainte-Anne, Université Paris Descartes, Paris, France. 3. PSL Research University, INSERM U830 Génétique et Biologie des Cancers Institut Curie, Paris, France. 4. Unité de génétique somatique, SIREDO pediatric oncology center, Institut Curie, Paris, France. 5. Département d'oncologie Pédiatrique adolescents Jeunes Adultes, Institut Curie, Paris, France, SIREDO pediatric oncology center, Institut Curie, Paris, France. 6. Institut Curie SIRIC - Laboratoire de Recherche Translationnelle en Oncologie Pédiatrique, Institut Curie, Paris, France. 7. Département de Biologie et Pathologie Médicales, Gustave Roussy, Université Paris-Saclay, Villejuif, France. 8. INSERM U1018, CESP, Université Paris-Sud, Université Paris-Saclay, Villejuif, France. 9. Service de Biostatistique et d'Epidémiologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France. 10. Unité d' Hémato-Immuno-Oncologie pédiatrique, CHU Toulouse, Toulouse, France. 11. Onco-hématologie pédiatrique, Hôpital d'Enfants, CHU Nancy, Nancy, France. 12. Hematology-Oncology Unit, Hôpital Universitaire des Enfants Reine Fabiola, ULB Université libre de Bruxelles, Brussels, Belgium. 13. Service de neurochirurgie pédiatrique, Hôpital Necker-Enfants malades, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 14. Département de Médecine Oncologique, Gustave Roussy, Université Paris-Saclay, Villejuif, France. 15. Laboratoire de génétique moléculaire, Département de bio-pathologie, Institut Bergonié, Bordeaux, France. 16. INSERM U1218, Université de Bordeaux, Bordeaux, France. 17. UFR des Sciences Pharmaceutiques, Université de Bordeaux, Bordeaux, France. 18. Unité Mixte de Recherche 8203 du Centre National de la Recherche Scientifique, Université Paris-Saclay, Villejuif, France.
Abstract
Background: Germline mutations of suppressor of fused homolog (SUFU) predispose to sonic hedgehog (SHH) medulloblastoma. Germline SUFU mutations have been reported in nevoid basal cell carcinoma syndrome (NBCCS), but little is known about the cancer risk and clinical spectrum. Methods: We performed a retrospective review of all patients with medulloblastoma and a germline SUFU mutation in France. Results: Twenty-two patients from 17 families were identified with medulloblastoma and a germline SUFU mutation (median age at diagnosis: 16.5 mo). Macrocrania was present in 20 patients, but only 5 met the diagnostic criteria for NBCCS. Despite treatment with surgery and chemotherapy, to avoid radiotherapy in all patients except one, the outcome was worse than expected for SHH medulloblastoma, due to the high incidence of local relapses (8/22 patients) and second malignancies (n = 6 in 4/22 patients). The 5-year progression-free survival and overall survival rates were 42% and 66%. Mutations were inherited in 79% of patients, and 34 additional SUFU mutation carriers were identified within 14 families. Medulloblastoma penetrance was incomplete, but higher than in Patched 1 (PTCH1) mutation carriers. Besides medulloblastoma, 19 other tumors were recorded among the 56 SUFU mutation carriers, including basal cell carcinoma (BCC) in 2 patients and meningioma in 3 patients. Conclusion: Germline SUFU mutations strongly predispose to medulloblastoma in the first years of life, with worse prognosis than usually observed for SHH medulloblastoma. The clinical spectrum differs between SUFU and PTCH1 mutation carriers, and BCC incidence is much lower in SUFU mutation carriers. The optimal treatment of SUFU mutation-associated medulloblastoma has not been defined.
Background: Germline mutations of suppressor of fused homolog (SUFU) predispose to sonic hedgehog (SHH) medulloblastoma. Germline SUFU mutations have been reported in nevoid basal cell carcinoma syndrome (NBCCS), but little is known about the cancer risk and clinical spectrum. Methods: We performed a retrospective review of all patients with medulloblastoma and a germline SUFU mutation in France. Results: Twenty-two patients from 17 families were identified with medulloblastoma and a germline SUFU mutation (median age at diagnosis: 16.5 mo). Macrocrania was present in 20 patients, but only 5 met the diagnostic criteria for NBCCS. Despite treatment with surgery and chemotherapy, to avoid radiotherapy in all patients except one, the outcome was worse than expected for SHH medulloblastoma, due to the high incidence of local relapses (8/22 patients) and second malignancies (n = 6 in 4/22 patients). The 5-year progression-free survival and overall survival rates were 42% and 66%. Mutations were inherited in 79% of patients, and 34 additional SUFU mutation carriers were identified within 14 families. Medulloblastoma penetrance was incomplete, but higher than in Patched 1 (PTCH1) mutation carriers. Besides medulloblastoma, 19 other tumors were recorded among the 56 SUFU mutation carriers, including basal cell carcinoma (BCC) in 2 patients and meningioma in 3 patients. Conclusion: Germline SUFU mutations strongly predispose to medulloblastoma in the first years of life, with worse prognosis than usually observed for SHH medulloblastoma. The clinical spectrum differs between SUFU and PTCH1 mutation carriers, and BCC incidence is much lower in SUFU mutation carriers. The optimal treatment of SUFU mutation-associated medulloblastoma has not been defined.
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