Clustered structural variant hotspots enable oncogenic addiction and plasticity in osteosarcoma
- 1Dana-Farber Cancer Institute
Abstract
The genomic landscape of osteosarcoma, the most common bone cancer worldwide, is among the most structurally complex of all human malignancies. The identification of recurrent and functionally consequential patterns has thus remained a challenge. Across 236 whole-genome sequencing osteosarcoma samples, we uncovered five genomic hotspots of clustered structural variation collectively altered in 58% of tumors. Four were associated with amplification of oncogenes ( MYC , CCND3 , CCNE1 , CDK4) , while the fifth mapped largely upstream of TP53 . Hotspot events showed coordinated patterns of co-occurrence and mutual exclusivity with each other and with tumor suppressor alterations, suggesting genomic context-specific selection. We found localized transcriptional dysregulation at hotspot event loci, and single cells harboring these events converged on a neural crest-like program, linking these structural alterations to a less differentiated cell state. These events were also detectable non-invasively through liquid biopsies and displayed ongoing structural evolution throughout disease progression, a finding with potential clinical utility. Our results provide novel insight into how complex rearrangements shape oncogenesis in osteosarcoma, with broader relevance to other cancers characterized by complex genomes.
Related
- RBFOX2 restrains oncogenic cell plasticity in Group 3 medulloblastoma
- Oncogenic transformation proceeds through a transient state of cellular plasticity constrained by lineage-specific barriers
- Altered proteome, astrocyte activation and reduced structural plasticity and progesterone sensitivity in the ventromedial hypothalamus were associated with disrupted sexual behavior in adult female mice exposed to environmentally relevant doses of phthalates
- Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Based Genome Editing in Inherited Cardiovascular Diseases: Therapeutic Advances, Emerging Editing Platforms, and Translational Challenges
- URGCP promotes osteosarcoma progression by regulating the ESCRT-III subunit CHMP4B
BibTeX
@misc{raman2026clustered,
title = {{Clustered structural variant hotspots enable oncogenic addiction and plasticity in osteosarcoma}},
author = {S. Raman and T. Kaltenbacher and D. Merrell and K. Prasad and Y. Tannaka and J. Weiss and E. Iannetta and B. Butaney and E. Jorswieck and A. Salem and L. Lazo De La Vega and E. Ceca and J. M. W. Wong and S. J. Forrest and K. Klega and M. Tanhaemami and C. A. Ricker and J. Wang and D. M. Diehl and J. Johnson and C. Cibulskis and K. Schlueter-Kuck and L. Q. Alley and N. B. Collins and C.-Z. Zhang and D. S. Shulman and B. D. Crompton and K. A. Janeway and G. Getz and R. Gillani},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.14.751472},
url = {https://www.biorxiv.org/content/10.64898/2026.09.14.751472v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Clustered structural variant hotspots enable oncogenic addiction and plasticity in osteosarcoma
AU - S. Raman
AU - T. Kaltenbacher
AU - D. Merrell
AU - K. Prasad
AU - Y. Tannaka
AU - J. Weiss
AU - E. Iannetta
AU - B. Butaney
AU - E. Jorswieck
AU - A. Salem
AU - L. Lazo De La Vega
AU - E. Ceca
AU - J. M. W. Wong
AU - S. J. Forrest
AU - K. Klega
AU - M. Tanhaemami
AU - C. A. Ricker
AU - J. Wang
AU - D. M. Diehl
AU - J. Johnson
AU - C. Cibulskis
AU - K. Schlueter-Kuck
AU - L. Q. Alley
AU - N. B. Collins
AU - C.-Z. Zhang
AU - D. S. Shulman
AU - B. D. Crompton
AU - K. A. Janeway
AU - G. Getz
AU - R. Gillani
PY - 2026
DA - 2026/09/14
PB - bioRxiv
DO - 10.64898/2026.09.14.751472
UR - https://www.biorxiv.org/content/10.64898/2026.09.14.751472v1
AB - The genomic landscape of osteosarcoma, the most common bone cancer worldwide, is among the most structurally complex of all human malignancies. The identification of recurrent and functionally consequential patterns has thus remained a challenge. Across 236 whole-genome sequencing osteosarcoma samples, we uncovered five genomic hotspots of clustered structural variation collectively altered in 58% of tumors. Four were associated with amplification of oncogenes ( MYC , CCND3 , CCNE1 , CDK4) , while the fifth mapped largely upstream of TP53 . Hotspot events showed coordinated patterns of co-occurrence and mutual exclusivity with each other and with tumor suppressor alterations, suggesting genomic context-specific selection. We found localized transcriptional dysregulation at hotspot event loci, and single cells harboring these events converged on a neural crest-like program, linking these structural alterations to a less differentiated cell state. These events were also detectable non-invasively through liquid biopsies and displayed ongoing structural evolution throughout disease progression, a finding with potential clinical utility. Our results provide novel insight into how complex rearrangements shape oncogenesis in osteosarcoma, with broader relevance to other cancers characterized by complex genomes.
ER -