bims-p53act 2026-03-22 papers

Front Genet. 2026 ;17 1680422

Mutant p53 and TP53 mutations in esophageal squamous cell carcinoma: consistency and diagnostic significance.

Background and objective: TP53 mutation is an initiating event in tumorigenesis in many cancers. Mutant p53 expression is an important manifestation of TP53 mutations, however, this association has not yet been confirmed in esophageal squamous cell carcinoma (ESCC). This study comprised three components. The first was screening for TP53 mutations using whole-exome sequencing (WES) or whole-genome sequencing (WGS). The second was identifying mutant p53 expression by immunohistochemical (IHC) staining to explore the association between mutant p53 expression and TP53 mutations. The third was assessing the diagnostic value of mutant p53 expression in patients with ESCC.
Methods: Eighteen fresh ESCC specimens were collected for WES. For cases without TP53 mutations detected by WES, WGS was performed to confirm the results and identify additional mutations. These samples underwent p53 IHC staining, and p53 expression was assessed independently by two senior pathologists. The Kappa coefficient was used to evaluate interobserver consistency. An additional 60 ESCC samples and corresponding adjacent tissues were collected for IHC staining. The chi-square test was used to assess the diagnostic value of p53 expression.
Results: WES revealed TP53 mutations in 13/18 cases. WGS of the five WES-negative samples identified TP53 mutations in four of them. Overall, TP53 mutations were detected in 17/18 cases (94.44%). Mutant p53 expression was present in all ESCC cases, and the consistency rate between TP53 mutation and p53 protein expression was 94.44% (17/18). In the combined WES + WGS cohort, mutant p53 expression was detected in 18/18 (100.00%) patients with ESCC. In the IHC cohort, mutant p53 expression was detected in 60/60 (100.00%) patients with ESCC. In both cohorts, Type I mutant p53 expression was the most common subtype, followed by Type IV. Type IV mutant expression was not observed in the WES + WGS cohort. The Kappa value for the two pathologists to was 0.954 (0.911-1.000). The sensitivity and specificity of mutant p53 expression for diagnosing ESCC were 1.00 (0.95-1.00) and 1.00 (0.95-1.00), respectively.
Conclusion: Mutant p53 expression can serve as an alternative marker for TP53 mutation screening used WES or WGS. Mutant p53 expression shows high sensitivity and specificity in distinguishing ESCC and can assist in differentiating benign from malignant esophageal lesions. Five mutant p53 expression subtypes were identified in this study; however, their clinical significance requires further investigation.

Keywords: TP53; consistency analysis; diagnostic value; esophageal squamous cell carcinoma; p53; whole exome sequencing

DOI: https://doi.org/10.3389/fgene.2026.1680422

Appl Immunohistochem Mol Morphol. 2026 Mar 19.

IHC p53 Performance in NordiQC: Recalibration of IHC Assays is Needed.

Kristi Bøgh Anderson, Søren Nielsen, Rasmus Røge.

The TP53 gene is the most frequently mutated gene in human cancers, with alterations occurring in ∼50% of all malignancies. When properly optimized, p53 immunohistochemistry (IHC) can serve as a reliable surrogate for detecting TP53 mutations. However, many laboratories struggle to identify p53 IHC reaction patterns beyond overexpression, particularly the absence, cytoplasmic, and wild-type patterns. As the clinical relevance of these additional patterns became recognized, NordiQC updated its assessment in 2021 to include wild-type and absence patterns, thereby increasing the complexity of p53 IHC and revealing widespread difficulties across laboratories. In this study, we analyze data from 6 consecutive NordiQC external quality assessment rounds from 2007 to 2024, covering 1,796 submitted p53 IHC assays. Our findings show that while most laboratories can reliably detect high antigen expression of overexpression, many protocols fail to adequately demonstrate low-level p53 expression, limiting the validity of the IHC assay. Ready-To-Use products, particularly when used according to manufacturer recommendations, performed suboptimally. These kits are calibrated exclusively to detect overexpression, leading to false-negative or too-weak results for other mutation-associated patterns. Our data represents the most comprehensive evaluation of p53 IHC assay performance to date. The findings underscore an urgent need to recalibrate p53 IHC protocols, with a special focus on improving analytical sensitivity and ensuring consistent use of both internal and external controls. Aligning IHC assays calibrated to identify the full spectrum of TP53 mutations, including those that result in absent and wild-type patterns, can significantly enhance the diagnostic accuracy of p53 IHC.

Keywords: NordiQC; TP53; analytical sensitivity; assay calibration; diagnostic accuracy; external quality assessment; immunohistochemistry optimization; laboratory performance; mutation-associated staining patterns; p53 immunohistochemistry

DOI: https://doi.org/10.1097/PAI.0000000000001314

Thorac Cancer. 2026 Mar;17(6): e70262

TP53 CpG Site Mutations Predict the Survival of First-Line Chemoimmunotherapy in Advanced Lung Adenocarcinoma.

Lige Wu, Zihua Zou, Yan Li, Xuezhi Hao, Jie Zhang, Jianming Ying, Puyuan Xing, Junling Li.

BACKGROUND: Chemoimmunotherapy is the first-line standard for advanced lung adenocarcinoma (LUAD) without driver mutations, but predictive biomarkers are still limited. TP53 is the most frequently mutated gene in LUAD, and its mutation subtypes affect treatment efficacy differently.
METHODS: This is a retrospective observational study. We retrospectively analyzed 133 patients with advanced LUAD who received first-line chemoimmunotherapy in our hospital. TP53 mutations were classified using a multidimensional approach. Key subtypes were identified through elastic-net and multivariate Cox regression analyses in clinical cohorts. The underlying mechanisms were further explored by transcriptomic and pathway analyses, including gene set variation analysis (GSVA) and immune cell deconvolution, using TCGA data.
RESULTS: An elastic-net Cox model within the TP53-mutant cohort identified three key features: TP53 variant allele frequency (VAF), CpG site mutation status, and dominant-negative effects (DNE)-loss-of-function (LOF) classification. Subsequent multivariate Cox regression in the full cohort confirmed that TP53 mutations at CpG sites were an independent favorable prognostic factor. Patients harboring CpG site mutations had significantly longer median progression-free survival (PFS) for first-line chemoimmunotherapy than both non-CpG-mutant and wild-type patients. Exploratory transcriptomic analyses revealed that CpG-mutant tumors were associated with an immune-activated tumor microenvironment (TME) characterized by enhanced T-Cell receptor (TCR) signaling, antigen presentation, IFN-γ signaling, and CD8+ T-cell infiltration, whereas non-CpG-mutant tumors exhibited a glycolytic metabolic profile and potentially reduced immune activity.
CONCLUSIONS: In conclusion, this study demonstrates that TP53 mutations at CpG sites define a distinct subgroup of patients with advanced LUAD who derive significantly greater PFS benefit from first-line chemoimmunotherapy.

Keywords: CpG site; TP53 mutation; chemoimmunotherapy; lung adenocarcinoma; predictive biomarker

DOI: https://doi.org/10.1111/1759-7714.70262

Front Oncol. 2025 ;15 1703503

Improving radiation therapy efficacy considering DNA repair, TP53 mutations, microscopic heterogeneity, and low- and high-dose apoptosis.

Anders Brahme.

All radiation types produce δ -rays of about a ≈1 keV or less that can impart MGy doses to 10-nm-size volumes of DNA. These events can produce severe dual double-strand breaks (DDSB) at the periphery of nucleosomes in single events particularly in heterochromatic DNA. These DDSBs are the most common multiply damaged sites, and their probabilities generally determine the biological effectiveness and therapeutic responses. The recent understanding that most normal tissues with intact TP53 genes generally are low-dose hypersensitive (LDHS) and low-dose apoptotic (LDA) implies that the well-known universal clinical fractionation window at ≈2 Gy/Fr defines the optimal tolerance level of most organs at risk and not the optimal tumor dose per fraction at least when using intensity-modulated radiation therapy (IMRT). Interestingly, practically all cancer cells are linked to genomic instability in some DNA repair, cell cycle, or growth control genes like TP53 that is affected in more than 50% of all tumors. Unfortunately, this often gives tumor cells a low-dose radiation-resistant (LDRR) phenotype. The fractionation window is due to the low-dose and linear energy transfer (LET) initiation of full DNA repair capability after ≈½ Gy or 18 DSB, and we should use this acquired repair advantage in normal tissues to its full extent up to ≈2.3 Gy where the high-dose apoptosis (HDA) starts to set in. Understanding quantum biological cure implies that light ions should truly have the lowest possible LET in normal tissues to retain the classical fractionation window but have a high LET only in the gross tumor region. Carbon ion therapy substantially benefits from the last ≈10 GyE of the treatment being delivered by low LET (electrons or photons) to minimize normal tissue damage, get a steepest possible dose response, and maximize complication-free cure. Interestingly, this also necessitates the use of the lightest ions with a low LET in normal tissues, allowing quantum biology-optimized molecular radiation therapy with He-Li-B ions, with minimal adverse therapeutic effect in normal tissues and the highest possible apoptosis, senescence, and cell kill in the tumor!

Keywords: TP53 damage sensors and modification sites; dual nucleosomal double-strand breaks; light ion radiation therapy; low-dose apoptosis; low-dose hyper-sensitivity; multiply damaged sites; optimal daily-weekly fractionation; therapy optimization

DOI: https://doi.org/10.3389/fonc.2025.1703503