The germline variants in DNA repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategies
Abstract Background 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 chem...
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doaj-a96162f4796c4a65bf39ef853fbba71b2020-11-24T20:58:33ZengBMCBMC Cancer1471-24072017-04-0117111110.1186/s12885-017-3211-yThe germline variants in DNA repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategiesJoanna Trubicka0Tomasz Żemojtel1Jochen Hecht2Katarzyna Falana3Dorota Piekutowska- Abramczuk4Rafał Płoski5Marta Perek-Polnik6Monika Drogosiewicz7Wiesława Grajkowska8Elżbieta Ciara9Elżbieta Moszczyńska10Bożenna Dembowska-Bagińska11Danuta Perek12Krystyna H. Chrzanowska13Małgorzata Krajewska-Walasek14Maria Łastowska15Department of Medical Genetics, The Children’s Memorial Health InstituteInstitute for Medical Genetics and Human Genetics, Charité Universitätsmedizin BerlinMax Planck Institute for Molecular GeneticsDepartment of Medical Genetics, The Children’s Memorial Health InstituteDepartment of Medical Genetics, The Children’s Memorial Health InstituteDepartment of Medical Genetics, Warsaw Medical UniversityDepartment of Oncology, The Children’s Memorial Health InstituteDepartment of Oncology, The Children’s Memorial Health InstituteDepartment of Pathology, The Children’s Memorial Health InstituteDepartment of Medical Genetics, The Children’s Memorial Health InstituteDepartment of Endocrinology and Diabetology, The Children’s Memorial Health InstituteDepartment of Oncology, The Children’s Memorial Health InstituteDepartment of Oncology, The Children’s Memorial Health InstituteDepartment of Medical Genetics, The Children’s Memorial Health InstituteDepartment of Medical Genetics, The Children’s Memorial Health InstituteDepartment of Pathology, The Children’s Memorial Health InstituteAbstract Background 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. Methods 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. Results 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. Conclusion 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.http://link.springer.com/article/10.1186/s12885-017-3211-yMedulloblastomaDNA repair genesToxicity |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Joanna Trubicka Tomasz Żemojtel Jochen Hecht Katarzyna Falana Dorota Piekutowska- Abramczuk Rafał Płoski Marta Perek-Polnik Monika Drogosiewicz Wiesława Grajkowska Elżbieta Ciara Elżbieta Moszczyńska Bożenna Dembowska-Bagińska Danuta Perek Krystyna H. Chrzanowska Małgorzata Krajewska-Walasek Maria Łastowska |
spellingShingle |
Joanna Trubicka Tomasz Żemojtel Jochen Hecht Katarzyna Falana Dorota Piekutowska- Abramczuk Rafał Płoski Marta Perek-Polnik Monika Drogosiewicz Wiesława Grajkowska Elżbieta Ciara Elżbieta Moszczyńska Bożenna Dembowska-Bagińska Danuta Perek Krystyna H. Chrzanowska Małgorzata Krajewska-Walasek Maria Łastowska The germline variants in DNA repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategies BMC Cancer Medulloblastoma DNA repair genes Toxicity |
author_facet |
Joanna Trubicka Tomasz Żemojtel Jochen Hecht Katarzyna Falana Dorota Piekutowska- Abramczuk Rafał Płoski Marta Perek-Polnik Monika Drogosiewicz Wiesława Grajkowska Elżbieta Ciara Elżbieta Moszczyńska Bożenna Dembowska-Bagińska Danuta Perek Krystyna H. Chrzanowska Małgorzata Krajewska-Walasek Maria Łastowska |
author_sort |
Joanna Trubicka |
title |
The germline variants in DNA repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategies |
title_short |
The germline variants in DNA repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategies |
title_full |
The germline variants in DNA repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategies |
title_fullStr |
The germline variants in DNA repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategies |
title_full_unstemmed |
The germline variants in DNA repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategies |
title_sort |
germline variants in dna repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategies |
publisher |
BMC |
series |
BMC Cancer |
issn |
1471-2407 |
publishDate |
2017-04-01 |
description |
Abstract Background 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. Methods 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. Results 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. Conclusion 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. |
topic |
Medulloblastoma DNA repair genes Toxicity |
url |
http://link.springer.com/article/10.1186/s12885-017-3211-y |
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