Defects in 8-oxo-guanine repair pathway cause high frequency of C > A substitutions in neuroblastoma
Marlinde L. van den Boogaard, Rurika Oka, Anne Hakkert, Linda Schild, Marli E. Ebus, Michael R. van Gerven, Danny A. Zwijnenburg, Piet Molenaar, Lieke Hoyng, M. Emmy M. Dolman, Anke H. W. Essing, Bianca Koopmans, Thomas Helleday, Jarno Drost, Ruben van Boxtel, Rogier Versteeg, Jan Köster, Jan J. Molenaar
Abstract
Significance The collection of large amounts of whole-genome sequencing data allowed for identification of mutational signatures, which are characteristic combinations of substitutions in the context of neighboring bases. The clinical significance of these mutational signatures is still largely unknown. In neuroblastoma, we showed that high levels of cytosine > adenine (C > A) substitutions are associated with poor survival. We identified that these high levels of C > A substitutions result from defects in 8-oxo-guanine repair, specifically from copy number loss of the DNA glycosylases MUTYH and OGG1 . The high frequency of C > A substitutions in neuroblastoma contributes to the increased adaptive capacity of these tumors. Thereby, we link basic molecular genetic mutation patterns to clinically significant tumor evolution processes.