In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 36 ( 2021-09-07)
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.2007898118
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2021
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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