Pediatric Medulloblastoma: The Role of Heterozygous Germ-Line Mutations in the NBN Gene

Chrzanowska, K; Trubicka, Joanna; Ciara, Elżbieta

doi:10.1007/978-94-007-4528-5_13

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“…This gene encodes the protein involved in DNA double-strand break repair, cell cycle checkpoint activation, telomere maintenance and meiotic recombination suggesting that molecular variants disrupting its function may lead to genome instability and carcinogenesis [28]. Furthermore, inactivation of proteins like RAD50 required for the homologous recombination machinery leads to defects in the nervous system development indicating that components of this system can play crucial role in development and progression of various neuro-oncological diseases [29]. The frequency of the molecular variants in RAD50 gene was, similarly to MSH2 , not determined in medulloblastoma patients up to now.…”

Section: Introductionmentioning

confidence: 99%

The germline variants in DNA repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategies

et al. 2017

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BackgroundThe 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.MethodsThe 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.ResultsWe 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.ConclusionOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3211-y) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%