Defects in 8-oxo-guanine repair pathway cause high frequency of C > A substitutions in neuroblastoma.

Autor:	van den Boogaard ML; Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands., Oka R; Oncode Institute, Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands., Hakkert A; Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands.; Department of Oncogenomics, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands., Schild L; Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands.; Department of Oncogenomics, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands., Ebus ME; Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands.; Department of Oncogenomics, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands., van Gerven MR; Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands., Zwijnenburg DA; Department of Oncogenomics, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands., Molenaar P; Department of Oncogenomics, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands., Hoyng LL; Department of Oncogenomics, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands., Dolman MEM; Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands.; Department of Oncogenomics, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands., Essing AHW; Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands., Koopmans B; Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands.; Department of Oncogenomics, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands., Helleday T; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, S-171 76 Stockholm, Sweden.; Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, S10 2RX Sheffield, United Kingdom., Drost J; Oncode Institute, Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands., van Boxtel R; Oncode Institute, Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands., Versteeg R; Department of Oncogenomics, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands., Koster J; Department of Oncogenomics, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands., Molenaar JJ; Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands; J.J.Molenaar@prinsesmaximacentrum.nl.; Department of Oncogenomics, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Sep 07; Vol. 118 (36).
DOI:	10.1073/pnas.2007898118
Abstrakt:	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. Competing Interests: The authors declare no competing interest. (Copyright © 2021 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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