MYC Activity Inference Captures Diverse Mechanisms of Aberrant MYC Pathway Activation in Human Cancers
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Abstract
c-MYC (MYC) is deregulated in more than 50% of all cancers. While MYC amplification is the most common MYC-deregulating event, many other alterations can increase MYC activity. We thus systematically investigated MYC pathway activity across different tumor types. Using a logistic regression framework, we established tumor type–specific, transcriptomic-based MYC activity scores that can accurately capture MYC activity. We show that MYC activity scores reflect a variety of MYC-regulating mechanisms, including MYCL and/or MYCN amplification, MYC promoter methylation, MYC mRNA expression, lncRNA PVT1 expression, MYC mutations, and viral integrations near the MYC locus. Our MYC activity score incorporates all of these mechanisms, resulting in better prognostic predictions compared with MYC amplification status, MYC promoter methylation, and MYC mRNA expression in several cancer types. In addition, we show that tumor proliferation and immune evasion are likely contributors to this reduction in survival. Finally, we developed a MYC activity signature for liquid tumors in which MYC translocation is commonly observed, suggesting that our approach can be applied to different types of genomic alterations. In conclusion, we developed a MYC activity score that captures MYC pathway activity and is clinically relevant. Implications: By using cancer type–specific MYC activity profiles, we were able to assess MYC activity across many more tumor types than previously investigated. The range of different MYC-related alterations captured by our MYC activity score can be used to facilitate the application of future MYC inhibitors and aid physicians to preselect patients for targeted therapy.
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Myc proteins play a critical role in pathways related to tumor development, including proliferation, apoptosis, differentiation, metabolism, and adaptive cancer resistance.
“Myc proteins, synthesized after transcription and translation of Myc gene, plays a critical role in pathways related to tumor development, including proliferation, apoptosis, differentiation, metabolism, and adaptive cancer resistance.412–414”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [414]
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Self-citationDuxfield, A., Garnham, R., Hutton, E., Dowle, A., Wills, J., Luzzi, S., Nelson, R., Lishman-Walker, E., Magee, R., Buskin, A., et al. (2025) · bioRxiv · doi:10.1101/2025.10.15.682547 · Cited by 2 · see citing works
Alahmari, A. A. (2025) · Biology · doi:10.3390/biology14121637
Gao, Y., Yuan, L., Ke, C., Pei, Z., Liu, X., Wu, R., Kui, X., & Zhang, Y. (2024) · Figshare · doi:10.6084/m9.figshare.26571958
Jari, M., Abdoli, S., Bazi, Z., Shamsabadi, F. T., Roshanmehr, F., & Shahbazi, M. (2024) · Figshare · doi:10.6084/m9.figshare.26675720
Jari, M., Abdoli, S., Bazi, Z., Shamsabadi, F. T., Roshanmehr, F., & Shahbazi, M. (2024) · Figshare · doi:10.6084/m9.figshare.26675723
Transcriptomic profile of MTUS1 -low TNBC reveals candidate therapeutic strategiesPreprint
Guichaoua, G., Collier, O., Rodrigues-Ferreira, S., Nahmias, C., & Stoven, V. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.05.22.727134
Cracking MYC addiction: Synthetic-lethal vulnerabilities for precision cancer therapy
Deng, K.-L., Hong, Z.-Y., Wang, Y.-X., Wu, Y., Zhang, W.-D., Luan, X., & Sun, Z. (2026) · Genes & Diseases · doi:10.1016/j.gendis.2026.102534
- Authors
- Schaafsma, E., Zhao, Y., Zhang, L., Li, Y., & Cheng, C.
- Affiliations
- Dartmouth College (US)
- Baylor College of Medicine (US)
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Cheng, Chao
- Venue
- Molecular Cancer Research
- Published
- 2021-03-01
- Volume
- 19
- Issue
- 3
- Pages
- 414-428
- ISSN
- 1541-7786 (ISSN-L)
- 1557-3125
- PMC
- PMC7925347
- OpenAlex
- W3110640063
- Cited by
- 12
- References
- 75
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 1 · 2021: 1
- FWCI
- 0.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- CPRIT (RR180061)
- NIH (1R21CA227996, T32 AI007363)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- MYC amplification, MYCN amplification, MYC mutations, viral integration, MYC translocation, liquid tumors, outcome prediction, tumor cell proliferation, immune evasion, MYC inhibitors, targeted therapy selection, gene expression signatures
- MeSH terms
- Breast Neoplasms, Gene Amplification, Humans, Models, Genetic, Neoplasms, Neuroblastoma, Prognosis, Survival Analysis, Proto-Oncogene Proteins c-myc, Gene Expression Profiling, Genomics
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