title: The germline variants in DNA repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategies.
abstract: The defects in DNA repair genes are potentially linked to development and response to therapy in medulloblastoma. Therefore the purpose of this study was to establish the spectrum and frequency of germline variants in selected DNA repair genes and their impact on response to chemotherapy in medulloblastoma patients.
  
  
  
  The following genes were investigated in 102 paediatric patients: MSH2 and RAD50 using targeted gene panel sequencing and NBN variants (p.I171V and p.K219fs*19) by Sanger sequencing. In three patients with presence of rare life-threatening adverse events (AE) and no detected variants in the analyzed genes, whole exome sequencing was performed. Based on combination of molecular and immunohistochemical evaluations tumors were divided into molecular subgroups. Presence of variants was tested for potential association with the occurrence of rare life-threatening AE and other clinical features.
  
  
  
  We have identified altogether six new potentially pathogenic variants in MSH2 (p.A733T and p.V606I), RAD50 (p.R1093*), FANCM (p.L694*), ERCC2 (p.R695C) and EXO1 (p.V738L), in addition to two known NBN variants. Five out of twelve patients with defects in either of MSH2, RAD50 and NBN genes suffered from rare life-threatening AE, more frequently than in control group (p = 0.0005). When all detected variants were taken into account, the majority of patients (8 out of 15) suffered from life-threatening toxicity during chemotherapy.
  
  
  
  Our results, based on the largest systematic study performed in a clinical setting, provide preliminary evidence for a link between defects in DNA repair genes and treatment related toxicity in children with medulloblastoma. The data suggest that patients with DNA repair gene variants could need special vigilance during and after courses of chemotherapy.
authors.affiliation: Department of Medical Genetics, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland. j.trubicka@ipczd.pl.|Department of Pathology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland. j.trubicka@ipczd.pl.
authors.forename: Joanna
authors.initials: J
authors.lastname: Trubicka
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.|Institute of Bioorganic Chemistry, Polish Academy of Sciences, 60-569, Poznan, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Żemojtel
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, 14195, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies, Charité Universitätsmedizin Berlin, 13353, Berlin, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hecht
authors.affiliation: Department of Medical Genetics, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Falana
authors.affiliation: Department of Medical Genetics, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Piekutowska-Abramczuk
authors.affiliation: Department of Medical Genetics, Warsaw Medical University, Warsaw, Poland.
authors.forename: Rafał
authors.initials: R
authors.lastname: Płoski
authors.affiliation: Department of Oncology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Perek-Polnik
authors.affiliation: Department of Oncology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Drogosiewicz
authors.affiliation: Department of Pathology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.|Department of Experimental and Clinical Pathology, Mossakowski Medical Research Centre Polish Academy of Sciences, A. Pawińskiego 5, 02-106, Warsaw, Poland.
authors.forename: Wiesława
authors.initials: W
authors.lastname: Grajkowska
authors.affiliation: Department of Medical Genetics, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Ciara
authors.affiliation: Department of Endocrinology and Diabetology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Moszczyńska
authors.affiliation: Department of Oncology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.
authors.forename: Bożenna
authors.initials: B
authors.lastname: Dembowska-Bagińska
authors.affiliation: Department of Oncology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.
authors.forename: Danuta
authors.initials: D
authors.lastname: Perek
authors.affiliation: Department of Medical Genetics, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.
authors.forename: Krystyna H
authors.initials: KH
authors.lastname: Chrzanowska
authors.affiliation: Department of Medical Genetics, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Krajewska-Walasek
authors.affiliation: Department of Pathology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.|Department of Experimental and Clinical Pathology, Mossakowski Medical Research Centre Polish Academy of Sciences, A. Pawińskiego 5, 02-106, Warsaw, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Łastowska
mesh_terms: D017766:Acid Anhydride Hydrolases; D000293:Adolescent; D000970:Antineoplastic Agents / Q000009:adverse effects; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004265:DNA Helicases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics / Q000473:pathology; D005090:Exodeoxyribonucleases / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D000073359:Exome Sequencing; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; C114331:EXO1 protein, human; D005090:Exodeoxyribonucleases; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; C518295:FANCM protein, human; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D045643:DNA Repair Enzymes
keywords: DNA repair genes; Medulloblastoma; Toxicity