1. Defects in 8-oxo-guanine repair pathway cause high frequency of C > A substitutions in neuroblastoma
- Author
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van den Boogaard, Marlinde L, Oka, Rurika, Hakkert, Anne, Schild, Linda, Ebus, Marli E, van Gerven, Michael R, Zwijnenburg, Danny A, Molenaar, Piet, Hoyng, Lieke L, Dolman, M Emmy M, Essing, Anke H W, Koopmans, Bianca, Helleday, Thomas, Drost, Jarno, van Boxtel, Ruben, Versteeg, Rogier, Koster, Jan, Molenaar, Jan J, Afd Pharmaceutics, Pharmaceutics, Afd Pharmaceutics, Pharmaceutics, Graduate School, AII - Cancer immunology, CCA - Cancer biology and immunology, and Oncogenomics
- Subjects
Male ,MUTYH ,Guanine ,DNA Repair ,Somatic cell ,mutational signatures ,Biology ,Polymorphism, Single Nucleotide ,DNA Glycosylases ,Cytosine ,neuroblastoma ,chemistry.chemical_compound ,Neuroblastoma ,Genetics ,medicine ,Humans ,Child ,OGG1 ,Gene ,8-oxo-guanine repair ,Multidisciplinary ,Guanosine ,Adenine ,Mutagenesis ,Biological Sciences ,medicine.disease ,Molecular biology ,Oxidative Stress ,chemistry ,DNA glycosylase ,Female ,Neoplasm Recurrence, Local ,DNA Damage - 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., 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.
- Published
- 2021
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