Tumor break load quantitates structural variant-associated genomic instability with biological and clinical relevance across cancers

Soufyan Lakbir; Renske de Wit; Ino de Bruijn; Ritika Kundra; Ramyasree Madupuri; Jianjiong Gao; Nikolaus Schultz; Gerrit A Meijer; Jaap Heringa; Remond J A Fijneman; Sanne Abeln

doi:10.1038/s41698-025-00922-9

Tumor break load quantitates structural variant-associated genomic instability with biological and clinical relevance across cancers

Soufyan Lakbir
, Renske de Wit
, Ino de Bruijn
, Ritika Kundra
, Ramyasree Madupuri
, Jianjiong Gao
, Nikolaus Schultz
, Gerrit A Meijer
, Jaap Heringa
, Remond J A Fijneman^*
, Sanne Abeln^*

^*Corresponding author for this work

Memorial Sloan-Kettering Cancer Center
Netherlands Cancer Institute
University of Groningen

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

Abstract

While structural variants (SVs) are a clear sign of genomic instability, they have not been systematically quantified per patient since declining costs have only recently enabled large-scale profiling. Therefore, the biological and clinical impact of high numbers of SVs in patients is unknown. We introduce tumor break load (TBL), defined as the sum of unbalanced SVs, as a measure for SV-associated genomic instability. Using pan-cancer data from TCGA, PCAWG, and CCLE, we show that a high TBL is associated with significant changes in gene expression in 26/31 cancer types that consistently involve upregulation of DNA damage repair and downregulation of immune response pathways. Patients with a high TBL show a higher risk of recurrence and shorter median survival times for 5/15 cancer types. Our data demonstrate that TBL is a biologically and clinically relevant feature of genomic instability that may aid patient prognostication and treatment stratification. For the datasets analyzed in this study, TBL has been made available in cBioPortal.

Original language	English
Article number	140
Journal	npj Precision Oncology
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41698-025-00922-9
Publication status	Published - 14 May 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

Funding

This study was supported by PPP Allowance [LSHM19027 and LSHM21018] made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. The funder played no role in study design, data collection, analysis, and interpretation of the data, or the writing of this manuscript. The authors would like to acknowledge the Research High Performance Computing (RHPC) facility of the Netherlands Cancer Institute (NKI). We thank Steven Ketelaars and Carmen Rubio-Alarcon for their valuable input on the interpretation of the immune pathway results and survival data analysis.

Funders	Funder number
PPP Allowance by Health~Holland, Top Sector Life Sciences Health	LSHM19027, LSHM21018

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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s41698-025-00922-9Final published version, 4.32 MBLicence: CC BY

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Lakbir, S., de Wit, R., de Bruijn, I., Kundra, R., Madupuri, R., Gao, J., Schultz, N., Meijer, G. A., Heringa, J., Fijneman, R. J. A., & Abeln, S. (2025). Tumor break load quantitates structural variant-associated genomic instability with biological and clinical relevance across cancers. npj Precision Oncology, 9( 1), Article 140. https://doi.org/10.1038/s41698-025-00922-9

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abstract = "While structural variants (SVs) are a clear sign of genomic instability, they have not been systematically quantified per patient since declining costs have only recently enabled large-scale profiling. Therefore, the biological and clinical impact of high numbers of SVs in patients is unknown. We introduce tumor break load (TBL), defined as the sum of unbalanced SVs, as a measure for SV-associated genomic instability. Using pan-cancer data from TCGA, PCAWG, and CCLE, we show that a high TBL is associated with significant changes in gene expression in 26/31 cancer types that consistently involve upregulation of DNA damage repair and downregulation of immune response pathways. Patients with a high TBL show a higher risk of recurrence and shorter median survival times for 5/15 cancer types. Our data demonstrate that TBL is a biologically and clinically relevant feature of genomic instability that may aid patient prognostication and treatment stratification. For the datasets analyzed in this study, TBL has been made available in cBioPortal.",

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AU - Madupuri, Ramyasree

AU - Gao, Jianjiong

AU - Schultz, Nikolaus

AU - Meijer, Gerrit A

AU - Heringa, Jaap

AU - Fijneman, Remond J A

AU - Abeln, Sanne

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AB - While structural variants (SVs) are a clear sign of genomic instability, they have not been systematically quantified per patient since declining costs have only recently enabled large-scale profiling. Therefore, the biological and clinical impact of high numbers of SVs in patients is unknown. We introduce tumor break load (TBL), defined as the sum of unbalanced SVs, as a measure for SV-associated genomic instability. Using pan-cancer data from TCGA, PCAWG, and CCLE, we show that a high TBL is associated with significant changes in gene expression in 26/31 cancer types that consistently involve upregulation of DNA damage repair and downregulation of immune response pathways. Patients with a high TBL show a higher risk of recurrence and shorter median survival times for 5/15 cancer types. Our data demonstrate that TBL is a biologically and clinically relevant feature of genomic instability that may aid patient prognostication and treatment stratification. For the datasets analyzed in this study, TBL has been made available in cBioPortal.

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Tumor break load quantitates structural variant-associated genomic instability with biological and clinical relevance across cancers

Abstract

Bibliographical note

Funding

UN SDGs

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