Complex structural variation is prevalent and highly pathogenic in pediatric solid tumors

Ianthe A.E.M. van Belzen; Marc van Tuil; Shashi Badloe; Alex Janse; Eugène T.P. Verwiel; Marcel Santoso; Sam de Vos; John Baker-Hernandez; Hindrik H.D. Kerstens; Nienke Solleveld-Westerink; Michael T. Meister; Jarno Drost; Marry M. van den Heuvel-Eibrink; Johannes H.M. Merks; Jan J. Molenaar; Weng Chuan Peng; Bastiaan B.J. Tops; Frank C.P. Holstege; Patrick Kemmeren; Jayne Y. Hehir-Kwa

doi:10.1016/j.xgen.2024.100675

Complex structural variation is prevalent and highly pathogenic in pediatric solid tumors

Ianthe A.E.M. van Belzen, Marc van Tuil, Shashi Badloe, Alex Janse, Eugène T.P. Verwiel, Marcel Santoso, Sam de Vos, John Baker-Hernandez, Hindrik H.D. Kerstens, Nienke Solleveld-Westerink, Michael T. Meister, Jarno Drost, Marry M. van den Heuvel-Eibrink, Johannes H.M. Merks, Jan J. Molenaar, Weng Chuan Peng, Bastiaan B.J. Tops, Frank C.P. Holstege, Patrick Kemmeren^*, Jayne Y. Hehir-Kwa^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

In pediatric cancer, structural variants (SVs) and copy-number alterations contribute to cancer initiation as well as progression, thereby aiding diagnosis and treatment stratification. Although suggested to be of importance, the prevalence and biological relevance of complex genomic rearrangements (CGRs) across pediatric solid tumors is largely unexplored. In a cohort of 120 primary tumors, we systematically characterized patterns of extrachromosomal DNA, chromoplexy, and chromothripsis across five pediatric solid cancer types. CGRs were identified in 56 tumors (47%), and in 42 of these tumors, CGRs affect cancer driver genes or result in unfavorable chromosomal alterations. This demonstrates that CGRs are prevalent and pathogenic in pediatric solid tumors and suggests that selection likely contributes to the structural variation landscape. Moreover, carrying CGRs is associated with more adverse clinical events. Our study highlights the potential for CGRs to be incorporated in risk stratification or exploited for targeted treatments.

Original language	English
Article number	100675
Journal	Cell genomics
Volume	4
Issue number	11
Early online date	14 Oct 2024
DOIs	https://doi.org/10.1016/j.xgen.2024.100675
Publication status	Published - 13 Nov 2024

Keywords

CGRs
chromoplexy
chromothripsis
complex genomic rearrangements
complex structural variation
ecDNA
extrachromosomal DNA
pediatric solid tumors
WGS
whole-genome sequencing

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PIIS2666979X24002945Final published version, 3.91 MBLicence: CC BY-NC-ND

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van Belzen, I. A. E. M., van Tuil, M., Badloe, S., Janse, A., Verwiel, E. T. P., Santoso, M., de Vos, S., Baker-Hernandez, J., Kerstens, H. H. D., Solleveld-Westerink, N., Meister, M. T., Drost, J., van den Heuvel-Eibrink, M. M., Merks, J. H. M., Molenaar, J. J., Peng, W. C., Tops, B. B. J., Holstege, F. C. P., Kemmeren, P., & Hehir-Kwa, J. Y. (2024). Complex structural variation is prevalent and highly pathogenic in pediatric solid tumors. Cell genomics, 4(11), Article 100675. https://doi.org/10.1016/j.xgen.2024.100675

@article{03667732812f4deda38e88dcaa42e6b9,

title = "Complex structural variation is prevalent and highly pathogenic in pediatric solid tumors",

abstract = "In pediatric cancer, structural variants (SVs) and copy-number alterations contribute to cancer initiation as well as progression, thereby aiding diagnosis and treatment stratification. Although suggested to be of importance, the prevalence and biological relevance of complex genomic rearrangements (CGRs) across pediatric solid tumors is largely unexplored. In a cohort of 120 primary tumors, we systematically characterized patterns of extrachromosomal DNA, chromoplexy, and chromothripsis across five pediatric solid cancer types. CGRs were identified in 56 tumors (47%), and in 42 of these tumors, CGRs affect cancer driver genes or result in unfavorable chromosomal alterations. This demonstrates that CGRs are prevalent and pathogenic in pediatric solid tumors and suggests that selection likely contributes to the structural variation landscape. Moreover, carrying CGRs is associated with more adverse clinical events. Our study highlights the potential for CGRs to be incorporated in risk stratification or exploited for targeted treatments.",

keywords = "CGRs, chromoplexy, chromothripsis, complex genomic rearrangements, complex structural variation, ecDNA, extrachromosomal DNA, pediatric solid tumors, WGS, whole-genome sequencing",

author = "{van Belzen}, {Ianthe A.E.M.} and {van Tuil}, Marc and Shashi Badloe and Alex Janse and Verwiel, {Eug{\`e}ne T.P.} and Marcel Santoso and {de Vos}, Sam and John Baker-Hernandez and Kerstens, {Hindrik H.D.} and Nienke Solleveld-Westerink and Meister, {Michael T.} and Jarno Drost and {van den Heuvel-Eibrink}, {Marry M.} and Merks, {Johannes H.M.} and Molenaar, {Jan J.} and Peng, {Weng Chuan} and Tops, {Bastiaan B.J.} and Holstege, {Frank C.P.} and Patrick Kemmeren and Hehir-Kwa, {Jayne Y.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = nov,

day = "13",

doi = "10.1016/j.xgen.2024.100675",

language = "English",

volume = "4",

number = "11",

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van Belzen, IAEM, van Tuil, M, Badloe, S, Janse, A, Verwiel, ETP, Santoso, M, de Vos, S, Baker-Hernandez, J, Kerstens, HHD, Solleveld-Westerink, N, Meister, MT, Drost, J, van den Heuvel-Eibrink, MM , Merks, JHM, Molenaar, JJ, Peng, WC, Tops, BBJ, Holstege, FCP, Kemmeren, P & Hehir-Kwa, JY 2024, 'Complex structural variation is prevalent and highly pathogenic in pediatric solid tumors', Cell genomics, vol. 4, no. 11, 100675. https://doi.org/10.1016/j.xgen.2024.100675

TY - JOUR

T1 - Complex structural variation is prevalent and highly pathogenic in pediatric solid tumors

AU - van Belzen, Ianthe A.E.M.

AU - van Tuil, Marc

AU - Badloe, Shashi

AU - Janse, Alex

AU - Verwiel, Eugène T.P.

AU - Santoso, Marcel

AU - de Vos, Sam

AU - Baker-Hernandez, John

AU - Kerstens, Hindrik H.D.

AU - Solleveld-Westerink, Nienke

AU - Meister, Michael T.

AU - Drost, Jarno

AU - van den Heuvel-Eibrink, Marry M.

AU - Merks, Johannes H.M.

AU - Molenaar, Jan J.

AU - Peng, Weng Chuan

AU - Tops, Bastiaan B.J.

AU - Holstege, Frank C.P.

AU - Kemmeren, Patrick

AU - Hehir-Kwa, Jayne Y.

PY - 2024/11/13

Y1 - 2024/11/13

N2 - In pediatric cancer, structural variants (SVs) and copy-number alterations contribute to cancer initiation as well as progression, thereby aiding diagnosis and treatment stratification. Although suggested to be of importance, the prevalence and biological relevance of complex genomic rearrangements (CGRs) across pediatric solid tumors is largely unexplored. In a cohort of 120 primary tumors, we systematically characterized patterns of extrachromosomal DNA, chromoplexy, and chromothripsis across five pediatric solid cancer types. CGRs were identified in 56 tumors (47%), and in 42 of these tumors, CGRs affect cancer driver genes or result in unfavorable chromosomal alterations. This demonstrates that CGRs are prevalent and pathogenic in pediatric solid tumors and suggests that selection likely contributes to the structural variation landscape. Moreover, carrying CGRs is associated with more adverse clinical events. Our study highlights the potential for CGRs to be incorporated in risk stratification or exploited for targeted treatments.

AB - In pediatric cancer, structural variants (SVs) and copy-number alterations contribute to cancer initiation as well as progression, thereby aiding diagnosis and treatment stratification. Although suggested to be of importance, the prevalence and biological relevance of complex genomic rearrangements (CGRs) across pediatric solid tumors is largely unexplored. In a cohort of 120 primary tumors, we systematically characterized patterns of extrachromosomal DNA, chromoplexy, and chromothripsis across five pediatric solid cancer types. CGRs were identified in 56 tumors (47%), and in 42 of these tumors, CGRs affect cancer driver genes or result in unfavorable chromosomal alterations. This demonstrates that CGRs are prevalent and pathogenic in pediatric solid tumors and suggests that selection likely contributes to the structural variation landscape. Moreover, carrying CGRs is associated with more adverse clinical events. Our study highlights the potential for CGRs to be incorporated in risk stratification or exploited for targeted treatments.

KW - CGRs

KW - chromoplexy

KW - chromothripsis

KW - complex genomic rearrangements

KW - complex structural variation

KW - ecDNA

KW - extrachromosomal DNA

KW - pediatric solid tumors

KW - WGS

KW - whole-genome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85207743989&partnerID=8YFLogxK

U2 - 10.1016/j.xgen.2024.100675

DO - 10.1016/j.xgen.2024.100675

M3 - Article

AN - SCOPUS:85207743989

SN - 2666-979X

VL - 4

JO - Cell genomics

JF - Cell genomics

IS - 11

M1 - 100675

ER -

Complex structural variation is prevalent and highly pathogenic in pediatric solid tumors

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Keywords

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