biostudies-literaturevan den Boogaard MLZonMW Vidi grantEuropean Research CouncilVilla Joep FoundationZonMwStichting Kinderen KankervrijOncode InstituteDutch Cancer Society (KWF)/Alpe d&apos;HuZes Bas Mulder Awarde2007898118https://www.ebi.ac.uk/biostudies/studies/S-EPMC8433536biostudies-literatureUnknown118(36)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 <i>OGG1</i> or <i>MUTYH</i> 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 <i>OGG1</i> or <i>MUTYH</i> show increased 8-oxoG levels compared to wild-type cells. We used CRISPR-Cas9 genome editing to create knockout clones of <i>MUTYH</i> and <i>OGGProceedings of the National Academy of Sciences of the United States of AmericaDefects in 8-oxo-guanine repair pathway cause high frequency of C > A substitutions in neuroblastoma.PMC843353691716482N/A10218van Gerven MRvan Boxtel RZwijnenburg DAEssing AHWKoster JHakkert ASchild LDrost Jvan den Boogaard MLEbus MEHoyng LLDolman MEMKoopmans BMolenaar JJHelleday TVersteeg ROka RMolenaar PfalseDefects in 8-oxo-guanine repair pathway cause high frequency of C > A substitutions in neuroblastoma.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 <i>OGG1</i> or <i>MUTYH</i> 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 <i>OGG1</i> or <i>MUTYH</i> show increased 8-oxoG levels compared to wild-type cells. We used CRISPR-Cas9 genome editing to create knockout clones of <i>MUTYH</i> and <i>OGG2021-01-01T00:00:00Z2021 Sep2026-05-08T16:39:21.976Z2025-06-01T00:57:18.491ZS-EPMC84335363447999310.1073/pnas.2007898118