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