Functional impact of the hyperduplication genomophenotype in high copy number endometrial cancer
High copy-number endometrial cancers (HCNECs) are dominated by excessive duplications scattered across the genome, termed here as the hyperduplication genomophenotype (HDGP). We identified locations and sizes of duplications in 171 endometrial cancer cases and designated 71 HCNEC cases as HDGP. We also investigated the response to the pan-ERBB inhibitor afatinib in a subset of HDGP-EC cases with <i>ERBB2/ERBB3</i> duplications using a patient-derived three-dimensional culture model. Our analysis demonstrates that beyond tandem duplications there is a more general pattern involving coordinated duplication of multiple distant regions of the genome, demonstrating preferential selectivity to overexpressed potential oncogenes within a broad network. This suggests that HDGP increases tumor fitness and resistance to therapy by perturbing important gene networks in concert rather than only driver genes, suggesting a mechanistic basis for the ineffectiveness of targeted drugs in these patients and highlighting the need for combination therapies in these highly aggressive cases.
Authors
- Panos Z. Anastasiadis (ORCID: https://orcid.org/0000-0003-4436-9435)
- Gabriella Schivardi
- Luigi Antonio De Vitis (ORCID: https://orcid.org/0000-0003-3778-8666)
- Sotiris Sotiriou (ORCID: https://orcid.org/0000-0002-6060-4995)
- Stephen J. Murphy (ORCID: https://orcid.org/0000-0002-8630-5897)
- Mitesh J. Borad (ORCID: https://orcid.org/0000-0003-2700-2658)
- Lindsey Kinsella
- George Vasmatzis (ORCID: https://orcid.org/0000-0002-3401-3497)
- Dorsay Sadeghian
- Ilaria Capasso
- Roberto Salvatori (ORCID: https://orcid.org/0000-0001-6495-2244)
- Sarah H. Johnson (ORCID: https://orcid.org/0000-0001-7412-5322)
- Tommaso Occhiali (ORCID: https://orcid.org/0000-0002-0316-1008)
- Ryan W. Feathers (ORCID: https://orcid.org/0000-0002-7970-7572)
- Andrea Mariani
- James B. Smadbeck (ORCID: https://orcid.org/0000-0002-8902-0950)
- Michael T. Barrett (ORCID: https://orcid.org/0000-0002-5646-1530)
- Leah Grcevich
- John C. Cheville (ORCID: https://orcid.org/0000-0002-8202-6268)
- S. John Weroha (ORCID: https://orcid.org/0000-0002-7130-7259)
- Abdulmohammad Pezeshki (ORCID: https://orcid.org/0000-0001-6229-871X)
- Mohamed F. Ali (ORCID: https://orcid.org/0000-0003-2409-362X)
- Alyssa M. Larish
- Faye R. Harris
- T. Dennis Berry
- Wan-Hsin Lin
- Alexa McCune
- Angela Florio
Institutions
- Mayo Clinic (US)
- Mayo Clinic in Arizona (US)
- Mayo Clinic in Florida (US)
Publication Details
- Journal
- iScience
- Published
- 2025-06-07
- DOI
- https://doi.org/10.1016/j.isci.2025.112850
- Primary Topic
- Endometrial and Cervical Cancer Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Mayo Clinic
- National Institute of Allergy and Infectious Diseases