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 L Hoyng, M Emmy M Dolman, Anke H W Essing, Bianca Koopmans, Thomas Helleday, Jarno Drost, Ruben van Boxtel, Rogier Versteeg, Jan Koster, Jan J Molenaar

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

Neuroblastomas are childhood tumors with frequent fatal relapses after induction treatment, which is related to tumor evolution with additional genomic events. Our whole-genome sequencing data analysis revealed a high frequency of somatic cytosine > adenine (C > A) substitutions in primary neuroblastoma tumors, which was associated with poor survival. We showed that increased levels of C > A substitutions correlate with copy number loss (CNL) of OGG1 or MUTYH Both genes encode DNA glycosylases that recognize 8-oxo-guanine (8-oxoG) lesions as a first step of 8-oxoG repair. Tumor organoid models with CNL of OGG1 or MUTYH show increased 8-oxoG levels compared to wild-type cells. We used CRISPR-Cas9 genome editing to create knockout clones of MUTYH and OGG1 in neuroblastoma cells. Whole-genome sequencing of single-cell OGG1 and MUTYH knockout clones identified an increased accumulation of C > A substitutions. Mutational signature analysis of these OGG1 and MUTYH knockout clones revealed enrichment for C > A signatures 18 and 36, respectively. Clustering analysis showed that the knockout clones group together with tumors containing OGG1 or MUTYH CNL. In conclusion, we demonstrate that defects in 8-oxoG repair cause accumulation of C > A substitutions in neuroblastoma, which contributes to mutagenesis and tumor evolution.

Originele taal-2Engels
TijdschriftProceedings of the National Academy of Sciences of the United States of America
Volume118
Nummer van het tijdschrift36
DOI's
StatusGepubliceerd - 7 sep. 2021

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