PRJNA721799
Defects in 8-oxo-Guanine repair pathway cause high frequency of C>A substitutions in neuroblastoma
Neuroblastoma are childhood tumors with frequent fatal relapses after induction treatment, which is related to tumor evolution with additional genomic events. Our whole genome sequencing (WGS) data analysis revealed a high frequency of somatic 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 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 copy number loss 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. WGS 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 copy number loss. 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.