bims-p53act 2026-03-29 papers

Genes (Basel). 2026 Feb 26. pii: 270. [Epub ahead of print]17(3):

The Regulation of p53 by Ubiquitination and Implications for Therapeutic Targeting in Colorectal Cancer.

Background: The turnaround of the tumor suppressor p53 protein, the guardian of the genome, is closely regulated to ensure avoidance of its untimely activation, which could lead to the demise of normal cells. Cancer cells often display mutations in the gene TP53 encoding for p53, which interferes with its normal function. Methods: The genomic series of colorectal cancer from the Cancer Genome Atlas (TCGA) was interrogated to discover genomic alterations and determine the mRNA expression of enzymes affecting p53 ubiquitination in colorectal cancers with wild-type and mutant TP53. Results: Genomic alterations of p53-regulating E3 ubiquitin ligases were uncommon in colorectal cancers, the most frequent being mutations in RCHY1. Several p53-regulating E3 ligases were well expressed in subsets of colorectal cancers, two of which, MDM2 and TRIM24, displayed higher mRNA expressions than the normal colorectal epithelia. The former was particularly upregulated in TP53 wild-type colorectal cancers, and the latter was upregulated in both wild-type and mutant TP53 cancers. Upregulation of TRIM24 in TP53 mutant cancers was observed independently of the type of mutations (gain-of-function or other). Among E3 ligases used in proteolysis-targeting chimeras (PROTACs), VHL was upregulated together with its E2-conjugating enzyme UBE2S in colorectal cancers. Conclusions: This survey of p53-targeting ubiquitin ligases provides a roadmap for potential therapeutic strategies working by promoting the destruction of the mutant protein or reactivating its normal function in TP53-mutated colorectal cancers and promoting p53 function by preventing degradation in TP53 wild-type cancers.

Keywords: gain-of-function; proteolysis targeting chimeras; ubiquitin conjugating enzymes; ubiquitin ligases; ubiquitination

DOI: https://doi.org/10.3390/genes17030270

Front Immunol. 2026 ;17 1771897

Effect of co-occurring mutations in TP53 gene and TERT promoter on the survival of bladder cancer patients.

Maria Lina Tornesello, Maria Carmela Piccirillo, Rosa Tambaro, Vittorio Simeon.

Background: Mutations in the TP53 gene and telomerase reverse transcriptase promoter (TERTp) are among the most frequent genetic alterations in bladder cancer, but the clinical impact of their co-occurrence has not been fully explored. In this study, we assessed the mutational landscape as well as the prognostic significance of concurrent TERTp and TP53 mutations in a cohort of bladder urothelial carcinoma patients.
Methods: Using data from the cBioPortal database, we retrospectively analysed primary bladder urothelial carcinoma cases profiled with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assays. We investigated the relationships between tumour mutational burden (TMB), microsatellite instability (MSI), and somatic mutations. The Kaplan-Meier method was used to calculate patient overall survival. Log-rank testing and multivariable Cox proportional hazards modelling were used to evaluate prognostic factors.
Results: Among the 1,111 cancer cases, 416 exhibited concurrent mutations in both TERTp and TP53, 387 harboured mutations exclusively in TERTp, 132 showed mutations only in the TP53 gene, and 176 cases were double wild-type for both genetic regions (wt/wt). Overall survival was significantly longer in the wt/wt group compared to TERTp (HR 1.83, 95% CI 1.27 - 2.62, P<0.001), to TP53 mutant alone (HR 1.84, 95% CI 1.19 - 2.85, P = 0.006) and to TERTp/TP53 (HR 2.32, 95% CI 1.63 - 3.31, P<0.001) mutant groups. The presence of TERTp and TP53 mutations was associated with higher tumour mutational burden (TMB ≥10 mutations/Mb) and increased microsatellite instability (MSI) scores (P < 0.001). The significant association between TERTp and TP53 mutations was independently validated in a separate cohort.
Conclusions: Bladder urothelial cancer can be stratified into biologically and clinically distinct subtypes on the basis of cancer driver mutations, with concomitant TERTp/TP53 nucleotide changes strongly linked to reduced patients' overall survival. These results suggest a potential cooperative interaction between mutant TERTp and TP53 in the pathogenesis of bladder cancer, highlighting their significance as prognostic biomarkers and promising targets for novel therapeutic strategies.

Keywords: TERT promoter mutations; TP53 mutations; bladder urothelial carcinoma; co-mutations; telomerase

DOI: https://doi.org/10.3389/fimmu.2026.1771897

Oncologist. 2026 Mar 23. pii: oyag104. [Epub ahead of print]

A retrospective analysis of taxane-based chemotherapy in small bowel adenocarcinoma.

Mir Lim, Nikhil Grandhi, Preksha Shah, Kanwal Raghav, Victoria Serpas, Maria Pia Morelli, Katrina Pedersen, Aparna Kalyan, Mohamed Salem, Ryan Huey, John Paul Shen, Huamin Wang, Hua Wang, Anjali Vinocha, Jane Thomas, Robert Wolff, Michael J Overman.

BACKGROUND: Small bowel adenocarcinoma (SBA) is molecularly distinct from colorectal and gastric cancers, yet treatment typically parallels colorectal cancer. We evaluated the activity of taxane-based therapy in the largest SBA cohort to date.
METHODS: We retrospectively reviewed SBA patients treated with taxane-based chemotherapy at MD Anderson Cancer Center from 1994-2024. Eligible patients had pathologic confirmation, received >1 treatment cycle, and had tumor response evaluation. Survival analyses were analyzed using Kaplan-Meier and Cox proportional hazard models.
RESULTS: Seventy patients were identified. Median age was 57, and 59% were male. Primary sites were duodenum (44%), jejunum (34%), and Ileum (16%). Metastatic sites included peritoneum (39%) and liver (31%). Common mutations were TP53 (63%), KRAS (47%), SMAD4 (24%), and APC (15%). Taxanes were administered as single agents (29%) or in combination (71%), most often in second-(40%) or third-line (33%) settings. Overall response rate was 24%. Median time to progression (mTTP) was 3.1 months (95% CI: 2.0-4.2) and median overall survival (mOS) was 8.7 months (95% CI: 7.4-10.1). Efficacy did not differ by treatment line, regimen type, or tumor site, but was significantly associated with TP53 status; response rate was 20% in TP53-mutated vs 45% in wild-type (P = 0.009), with mTTP 2.5 vs 4.9 months (P = 0.009) and mOS 7.3 vs 10.6 months (P = 0.002). On multivariable analysis, TP53 mutation predicted worse outcomes.
CONCLUSION: Taxane-based therapy demonstrated activity in metastatic SBA, with 24% response and 3.1-month mTTP. TP53 mutation may be a negative predictive marker for taxane efficacy. These findings support prospective investigation in metastatic SBA.

Keywords: SBA; Small bowel adenocarcinoma; TP53; Taxane; chemotherapy; taxane

DOI: https://doi.org/10.1093/oncolo/oyag104

Curr Oncol. 2026 Mar 21. pii: 178. [Epub ahead of print]33(3):

Interplay Between p53 and Wnt/β-Catenin Signaling in Colorectal Cancer: Associations with Mismatch Repair Status, Tumor Microenvironment, and Clinicopathological Outcomes.

Seiya Chiba, Shu Oikawa, Hiroyuki Mitomi, Yosuke Sasaki, Takahiro Hobo, Takuya Terunuma, Yumika Takano, Marin Hojo, Toshiko Yamochi, Noboru Yokoyama.

The interplay between TP53 alterations and Wnt/β-catenin signaling in colorectal cancer (CRC) remains unclear regarding mismatch repair (MMR) status, tumor budding (TB), poorly differentiated cluster (PDC), and prognosis. We analyzed 146 resected CRC cases, quantifying p53, Wnt3, and β-CTN indices and assessing MMR by PMS2 and MSH6 immunohistochemistry. p53 overexpression was associated with younger patients, left-sided tumors, nodal metastasis, and advanced stage, whereas wild-type tumors showed more mucinous differentiation. Deficient MMR was enriched among wild-type p53 cases. Principal component analysis identified distinct axes defined by p53, Wnt3, and β-CTN. Despite comparable Wnt3 levels, nuclear β-CTN accumulation was enhanced in tumors with aberrant (overexpression or null) p53 tumors, with increased TB and PDC indices. Low nuclear β-CTN independently predicted recurrence in stage I-III disease and worse overall survival in proficient MMR tumors (HR 3.07 and 2.52; p = 0.03 for both). A composite score integrating p53 binary status (aberrant vs. wild) with Wnt3 and whole β-CTN indices predicted survival beyond stage; each 1-point increase conferred a 2.56- and 1.77-fold higher risk of cancer-specific and overall mortality (p = 0.004 and 0.04). These findings suggest that p53 dysfunction is associated with alterations in Wnt/β-CTN signaling and that integrating signaling markers with staging may improve prognostic assessment in colorectal cancer.

Keywords: Wnt/β-catenin signaling; colorectal cancer; image analysis; mismatch repair; p53; poorly differentiated cluster; prognosis; tumor budding

DOI: https://doi.org/10.3390/curroncol33030178

Mutagenesis. 2026 Mar 23. pii: geag014. [Epub ahead of print]

Induction of genotoxic damage and ROS production in HCT116 TP53+/+ and HCT116TP53-/- colorectal cancer cell lines by anticancer drugs.

Chiara Naldoni, Irene Guidotti, Matilde Matteoli, Domenica Di Bello, Viola Scatolini, Veronica Esposti, Aurora Falaschi, Roberto Scarpato.

Reactive oxygen species (ROS) play a dual role in cancer biology, contributing to both tumor progression and therapeutic responses. Many chemotherapeutic agents exert their cytotoxic effects through ROS generation, although the extent and biological relevance of this process remain influenced by cellular context, including the functional status of tumor suppressor genes such as TP53. In this study, we investigated the induction of genomic damage and oxidative stress in two isogenic human colorectal cancer cell lines - HCT116TP53+/+ and HCT116TP53-/- - after exposure to four commonly used anticancer agents: oxaliplatin (OXA), irinotecan (IRI), paclitaxel (PAC), and 5-fluorouracil (5-FU). Drug concentrations were selected to ensure cell viability while inducing genotoxicity. Genome damage was assessed by micronucleus (MN) assay. ROS production was measured using the BODIPY581/591 C11 lipid peroxidation fluorescent probe. Our results showed that OXA and IRI induced both significant MN formation and robust ROS production in a dose-dependent manner, while PAC predominantly triggered genomic damage with limited ROS generation. Conversely, 5-FU exhibited marginal (or no) effect on both endpoints. Notably, with regard to the extent of ROS accumulation and MN induction, no significant differences were detected under the tested conditions between the two HCT116 cell lines. This suggests that under non-cytotoxic conditions, p53 is not a critical modulator of oxidative responses to these agents. Overall, our data reveal a drug-specific pattern of genome and oxidative damage in HCT116 colorectal cancer cells, emphasizing the importance of considering drug mechanism of action in evaluating redox responses. These insights may contribute to the development of targeted combinatorial therapies aimed at modulating oxidative stress, especially in TP53-mutated tumors.

DOI: https://doi.org/10.1093/mutage/geag014