@article{5ffeb28848d44163b342ade34ccabd77,
title = "Defects in 8-oxo-guanine repair pathway cause high frequency of C > A substitutions in neuroblastoma",
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.",
keywords = "8-oxo-guanine repair, MUTYH, Mutational signatures, Neuroblastoma, OGG1",
author = "{van den Boogaard}, {Marlinde L.} and Rurika Oka and Anne Hakkert and Linda Schild and Ebus, {Marli E.} and {van Gerven}, {Michael R.} and Zwijnenburg, {Danny A.} and Piet Molenaar and Hoyng, {Lieke L.} and Dolman, {Emmy M. M.} and Essing, {Anke H. W.} and Bianca Koopmans and Thomas Helleday and Jarno Drost and {van Boxtel}, Ruben and Rogier Versteeg and Jan Koster and Molenaar, {Jan J.}",
note = "Funding Information: ACKNOWLEDGMENTS. The research in this paper was supported by grants from the Villa Joep Foundation and KIKA, by a European Union European Research Council Advanced grant (PREDICT) to J.J.M., by a ZonMW Vidi grant (91716482) to J.J.M., by the European Union{\textquoteright}s Horizon 2020 program (grant 826121, iPC project) to J.J.M., by the Dutch Cancer Society (KWF)/Alpe d{\textquoteright}HuZes Bas Mulder Award (KWF/Alpe d{\textquoteright}HuZes, 10218) to J.D., by the Swedish Childhood Cancer Fund (PR2018-0095) to T.H., and by the Oncode Institute to J.D. and R.v.B. Funding Information: The research in this paper was supported by grants from the Villa Joep Foundation and KIKA, by a European Union European Research Council Advanced grant (PREDICT) to J.J.M., by a ZonMW Vidi grant (91716482) to J.J.M., by the European Union's Horizon 2020 program (grant 826121, iPC project) to J.J.M., by the Dutch Cancer Society (KWF)/Alpe d'HuZes Bas Mulder Award (KWF/Alpe d'HuZes, 10218) to J.D., by the Swedish Childhood Cancer Fund (PR2018-0095) to T.H., and by the Oncode Institute to J.D. and R.v.B. Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = sep,
day = "7",
doi = "https://doi.org/10.1073/pnas.2007898118",
language = "English",
volume = "118",
journal = "PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA",
issn = "0027-8424",
publisher = "National Acad Sciences",
number = "36",
}