Evolution of oncogene amplification across 86,000 cancer cell genomes
High-level copy-number (CN) amplification (HLAMP) is a major mechanism of oncogene activation in human cancer. Despite progress in therapeutically targeting HLAMPs, the processes underlying HLAMP evolution are incompletely understood, leaving critical knowledge gaps in their etiology and mechanisms of therapeutic response. To address this, we analyzed using novel computational approaches, the evolutionary trajectories of HLAMP in single-cell whole-genome sequencing of 86,239 cancer cells from 94 patients and 8 experimental systems. We found that two common etiologies of oncogene amplification-intrachromosomal amplification (ICamp) and extrachromosomal circular DNA (ecDNA)-lead to distinct CN distributions across cells in amplitude, variance and clone specificity. Notably, ICamp events exhibited widespread subclonal specificity, indicating their dynamic evolution through numeric or structural modulation associated with clonal expansions. In contrast, ecDNAs exhibited higher cell-to-cell CN variation linked to structural rearrangements, whereby complex ecDNA architectures were resolved at single-nucleotide resolution in individual cell genomes. Through joint analysis of ecDNA structure and their cellular abundance, we observed both divergent and convergent modes of ecDNA evolution shaped by DNA damage, selection, and chromosomal re-integration. Finally, modeling single-cell distributions of ecDNAs substantially improved bulk genome-graph based predictions, revealing that ecDNA prevalence is tissue-type specific, rather than broadly shared across cancer types, with implications for ecDNA-directed therapy.
Authors
- Esther Redín (ORCID: https://orcid.org/0000-0001-9539-7298)
- Matthew A. Myers (ORCID: https://orcid.org/0000-0002-9337-5180)
- Eliyahu Havasov
- Asher Preska Steinberg (ORCID: https://orcid.org/0000-0002-8694-7224)
- Kenny Kwok Hei Yu (ORCID: https://orcid.org/0000-0002-2394-4990)
- Àlvaro Quintanal-Villalonga (ORCID: https://orcid.org/0000-0002-7234-3446)
- Neeman Mohibullah
- Andrea Ventura (ORCID: https://orcid.org/0000-0003-4320-9907)
- Nicole Rusk (ORCID: https://orcid.org/0000-0003-2663-6288)
- Lee Jc (ORCID: https://orcid.org/0000-0002-1502-8693)
- Michelle Wu (ORCID: https://orcid.org/0000-0001-6889-8345)
- Caitlin Timmons (ORCID: https://orcid.org/0000-0003-4118-4902)
- Kerstin Thol (ORCID: https://orcid.org/0000-0002-4624-118X)
- Parvathy Manoj (ORCID: https://orcid.org/0000-0002-1121-0121)
- Eric G. Sun (ORCID: https://orcid.org/0000-0002-9109-1969)
- Melissa A. Yao (ORCID: https://orcid.org/0000-0002-2274-6925)
- Seongmin Choi (ORCID: https://orcid.org/0000-0001-9722-1800)
- C M Rudin
- Samuel Aparício (ORCID: https://orcid.org/0000-0002-0487-9599)
- Viviane Tabar (ORCID: https://orcid.org/0000-0002-1284-1670)
- Duaa H. Al-Rawi (ORCID: https://orcid.org/0000-0002-9218-6513)
- Marc Williams (ORCID: https://orcid.org/0000-0001-5524-4174)
- Stephen Martis (ORCID: https://orcid.org/0000-0003-1735-2347)
- Sohrab P. Shah
- Cheryl Zi Jin Phua
- Mark M. Awad
- P. Razavi
- Andrew Mcpherson
- Natasha Rekhtman
- Sohrab Salehi
- Jin Lee
- Jake June-Koo Lee
- Helena A. Yu
Institutions
- Memorial Sloan Kettering Cancer Center (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-02-14
- DOI
- https://doi.org/10.64898/2026.02.12.705658
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Defense
- Memorial Sloan-Kettering Cancer Center
- Ovarian Cancer Research Alliance
- Cycle for Survival
- National Institutes of Health
- National Cancer Institute