Research output: Contribution to journal › Article › Academic › peer-review
Defects in 8-oxo-guanine repair pathway cause high frequency of C > A substitutions in neuroblastoma. / van den Boogaard, Marlinde L.; Oka, Rurika; Hakkert, Anne et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 118, No. 36, e2007898118, 07.09.2021.Research output: Contribution to journal › Article › Academic › peer-review
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TY - JOUR
T1 - Defects in 8-oxo-guanine repair pathway cause high frequency of C > A substitutions in neuroblastoma
AU - van den Boogaard, Marlinde L.
AU - Oka, Rurika
AU - Hakkert, Anne
AU - Schild, Linda
AU - Ebus, Marli E.
AU - van Gerven, Michael R.
AU - Zwijnenburg, Danny A.
AU - Molenaar, Piet
AU - Hoyng, Lieke L.
AU - Dolman, Emmy M. M.
AU - Essing, Anke H. W.
AU - Koopmans, Bianca
AU - Helleday, Thomas
AU - Drost, Jarno
AU - van Boxtel, Ruben
AU - Versteeg, Rogier
AU - Koster, Jan
AU - Molenaar, Jan J.
N1 - 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’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. 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: © 2021 National Academy of Sciences. All rights reserved.
PY - 2021/9/7
Y1 - 2021/9/7
N2 - 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.
AB - 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.
KW - 8-oxo-guanine repair
KW - MUTYH
KW - Mutational signatures
KW - Neuroblastoma
KW - OGG1
UR - http://www.scopus.com/inward/record.url?scp=85114612415&partnerID=8YFLogxK
U2 - 10.1073/pnas.2007898118
DO - 10.1073/pnas.2007898118
M3 - Article
C2 - 34479993
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 36
M1 - e2007898118
ER -
ID: 19718448