Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 36, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2007898118|1of9
Keywords
neuroblastoma; 8-oxo-guanine repair; MUTYH; OGG1; mutational signatures
Categories
Funding
- Villa Joep Foundation
- KIKA
- European Union European Research Council Advanced grant (PREDICT)
- ZonMW Vidi grant [91716482]
- European Union's Horizon 2020 program [826121]
- Dutch Cancer Society (KWF) /Alpe d'HuZes Bas Mulder Award (KWF/Alpe d'HuZes) [10218]
- Swedish Childhood Cancer Fund [PR2018-0095]
- Oncode Institute
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Neuroblastomas, childhood tumors, exhibit a high frequency of somatic C > A substitutions associated with poor survival. Defects in 8-oxoG repair in neuroblastoma lead to accumulation of C > A substitutions, contributing to mutagenesis and tumor evolution.
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.
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