Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer.
5 affiliations
- 1Department of Medicine, The MetroHealth System, Case Western Reserve University, 2500 Metro Health Drive, Cleveland, OH 44109, USA.
- 2Hormel Institute, University of Minnesota 801 16th Ave NE, Austin, MN 55912, USA.
- 3Gene and Cell Therapy Institute, The MetroHealth System, Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, OH 44109, USA.
- 4Division of Hematology, Mayo Clinic, 200 1st St SW, Rochester, MN 55901, USA.
- 5Department of Genetics and Genome Sciences, Case Western Reserve University Medical School, 2109 Adelbert Road, Cleveland, OH 44106, USA.
Abstract
Although multi-hit TP53 mutations correlate with rapid disease progression, treatment resistance, recurrence, and poor survival, their occurrence within an individual TP53 gene molecule (cbTP53) remains unexplored. Consequently, the impact of cbTP53 on protein conformation, transcriptional architecture, and oncogenicity is unknown. We show that cbTP53 with combined mutations (Y220C+R248Q+R282Q) does not drastically alter local stability or structural conformation, but significantly affects TP53 binding to DNA promoters comparing it to a single Y220C mutation. Functionally, cbTP53 promotes divergent cellular phenotypes, characterized by enhanced cell proliferation, increased formation of multicellular tumor spheroids (MCTS) and spheroids, altered responses to chemotherapeutic drugs (e.g., cisplatin, carboplatin) and p53 inhibitors (e.g., MB710, PK11007), and increased resistance to carboplatin-induced DNA damage. Furthermore, cbTP53 is linked to distinct immune cell profiles (e.g., CD4+ and CD8+ T cells, nature killer cells, dendritic cells), more circulating tumor cells, a higher rate of tumor engraftment, and an increased number of lung tumor nodules. Mechanistically, introduction of R248Q/R282Q mutations changes 42.7% of Y220C-regulated gene expression, and cbTP53 (vs Y220C) owns a distinctive transcriptomic signature with 1,004 up- and 1,747 down-regulated genes. cbTP53 shows the enhanced binding affinity in the promoters of inflammatory cytokines, leading to their increased production. This study establishes causative and mechanistic links of cbTP53 to lung aggressive cancer metastasis and disease progression, providing a novel perspective on the genetics of TP53 mutations in cancer.
Related
- A chimeric bladder tumor in a renal transplant recipient: the oncogenic convergence of JC virus and PIK3CA mutation
- Non-coding RNA 7SK drives tumor resistance by coupling local oncogenic activation with global transcriptional repression
- Determining malignancy in thyroid nodules featuring anterior macrocalcifications with strong posterior acoustic shadowing: the combined utility of US-FNA and BRAF V600E mutation analysis
- Efficacy and safety of immune checkpoint inhibitors combined with TKIs for recurrent or metastatic cervical cancer with PIK3CA mutation
- Effects of Steam Explosion Combined with Ultrafine Grinding on the Physicochemical Properties, Antioxidant Capacity, and Volatile Profiles of Morchella sextelata Stipe Powders.
BibTeX
@article{bian2026combined,
title = {{Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer.}},
author = {Sicheng Bian and Huiqin Bian and Hiroaki Koyama and Dmytro Kompaniiets and William Tse and Mithun V Shah and Aref Al-Kali and Alexander Miron and Bin Liu and Shujun Liu},
journal = {International journal of biological sciences},
year = {2026},
month = sep,
doi = {10.7150/ijbs.131687},
url = {https://europepmc.org/article/MED/42910175},
note = {CC BY},
}
RIS
TY - JOUR
TI - Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer.
AU - Sicheng Bian
AU - Huiqin Bian
AU - Hiroaki Koyama
AU - Dmytro Kompaniiets
AU - William Tse
AU - Mithun V Shah
AU - Aref Al-Kali
AU - Alexander Miron
AU - Bin Liu
AU - Shujun Liu
PY - 2026
DA - 2026/09/10
JO - International journal of biological sciences
DO - 10.7150/ijbs.131687
UR - https://europepmc.org/article/MED/42910175
AB - Although multi-hit TP53 mutations correlate with rapid disease progression, treatment resistance, recurrence, and poor survival, their occurrence within an individual TP53 gene molecule (cbTP53) remains unexplored. Consequently, the impact of cbTP53 on protein conformation, transcriptional architecture, and oncogenicity is unknown. We show that cbTP53 with combined mutations (Y220C+R248Q+R282Q) does not drastically alter local stability or structural conformation, but significantly affects TP53 binding to DNA promoters comparing it to a single Y220C mutation. Functionally, cbTP53 promotes divergent cellular phenotypes, characterized by enhanced cell proliferation, increased formation of multicellular tumor spheroids (MCTS) and spheroids, altered responses to chemotherapeutic drugs (e.g., cisplatin, carboplatin) and p53 inhibitors (e.g., MB710, PK11007), and increased resistance to carboplatin-induced DNA damage. Furthermore, cbTP53 is linked to distinct immune cell profiles (e.g., CD4+ and CD8+ T cells, nature killer cells, dendritic cells), more circulating tumor cells, a higher rate of tumor engraftment, and an increased number of lung tumor nodules. Mechanistically, introduction of R248Q/R282Q mutations changes 42.7% of Y220C-regulated gene expression, and cbTP53 (vs Y220C) owns a distinctive transcriptomic signature with 1,004 up- and 1,747 down-regulated genes. cbTP53 shows the enhanced binding affinity in the promoters of inflammatory cytokines, leading to their increased production. This study establishes causative and mechanistic links of cbTP53 to lung aggressive cancer metastasis and disease progression, providing a novel perspective on the genetics of TP53 mutations in cancer.
SN - 1449-2288
ER -