Characterizing genomic differences of human cancer stratified by the TP53 mutation status

Abstract Objectives The tumor suppressor gene TP53 is the most commonly mutated gene in human cancer, but mutations in TP53 do not just result in loss of tumor suppressor function, they can also promote cancer progression by altering cellular iron acquisition and metabolism. A newly identified role for TP53 in the mediation of iron homeostasis and cancer cell survival lies in the ability for TP53 to protect against ferroptosis, a form of iron mediated cell death. The purpose of this study was to determine the extent to which TP53 mutation status effects iron-mediated cell death in response to ferroptosis induction. We also measured TP53 dependent differences in iron regulatory protein (IRP) RNA binding activity to begin to clarify the mechanisms by which TP53 mutation status may influence sensitivity to ferroptosis. Methods Using H1299 cells, which are null for TP53, we generated cell lines expressing either a tetracycline inducible wild-type TP53 gene, or a representative mutated TP53 gene from exemplary “hotspot” mutations in the DNA binding domain (R248, R273, R282, G245, R249 and R175). These six mutation types were selected because they represent 25% of all TP53 mutations in human cancer. To determine the influence of TP53 mutation status on sensitivity to ferroptotic cell death, we treated cells with erastin, a potent inducer of ferroptosis and measured differences in cell viability between these cell lines using PrestoBlue cell viability reagent. To assess mutant TP53-depenent differences in IRP RNA binding activity during ferroptosis we measured differences in IRP RNA binding activity via Electrophoretic Mobility-Shift Assay. Results We found that TP53 mutants (R273, R248, R175, G245, and R249) were significantly less viable (P < 0.05) after initiation of ferroptosis compared to cells expressing WT TP53. Following ferroptosis induction, we observed a significant (P < 0.05) increase in IRP RNA binding in G245, R248, and R175 mutants. Conclusions Our preliminary analyses indicate that TP53 mutants may be more sensitive to ferroptosis, but IRPs do not seem to be solely responsible for the increase in iron during ferroptotic cell death. Furthermore, ferroptosis may be a potential therapeutic target for cancers with these TP53 mutations but further investigation is warranted. Funding Sources Internal funding at Oklahoma State University.

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Analysis of TP53 Mutation Status in Human Cancer Cell Lines: A Reassessment

Human Mutation ◽

10.1002/humu.22556 ◽

2014 ◽

Vol 35 (6) ◽

pp. 756-765 ◽

Cited By ~ 81

Author(s):

Bernard Leroy ◽

Luc Girard ◽

Antoinette Hollestelle ◽

John D. Minna ◽

Adi F. Gazdar ◽

...

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Tp53 Mutation ◽

Human Cancer ◽

Cancer Cell Lines ◽

Human Cancer Cell ◽

Mutation Status ◽

Human Cancer Cell Lines

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P04.16 TP53 mutations in codon 273 is predictive of overall survival in astrocytoma patients

Neuro-Oncology ◽

10.1093/neuonc/noz126.111 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii32-iii32

Author(s):

H Noor ◽

R Rapkins ◽

K McDonald

Keyword(s):

Overall Survival ◽

Tp53 Mutation ◽

Progression Free Survival ◽

Low Grade Glioma ◽

Low Grade ◽

Wild Type ◽

Mutation Status ◽

Free Survival ◽

Tp53 Mutations ◽

Fresh Frozen

Abstract BACKGROUND Tumour Protein 53 (TP53) is a tumour suppressor gene that is mutated in at least 50% of human malignancies. The prevalence of TP53 mutation is much higher in astrocytomas with reports of up to 75% TP53 mutant cases. Rare cases of TP53 mutation also exist in oligodendroglial tumours (10–13%). P53 pathway is therefore an important factor in low-grade glioma tumorigenesis. Although the prognostic impact of TP53 mutations has been studied previously, no concrete concordance were reached between the studies. In this study, we investigated the prognostic effects of TP53 mutation in astrocytoma and oligodendroglioma. MATERIAL AND METHODS A cohort of 65 matched primary and recurrent fresh frozen tumours were sequenced to identify hotspot exons of TP53 mutation. Exons 1 to 10 were sequenced and pathogenic mutations were mostly predominant between Exons 4 and 8. The cohort was further expanded with 78 low grade glioma fresh frozen tissues and hotspot exons were sequenced. Selecting only the primary tumour from 65 matched tumours, a total of 50 Astrocytoma cases and 51 oligodendroglioma cases were analysed for prognostic effects of TP53. Only pathogenic TP53 mutations confirmed through COSMIC and NCBI databases were included in the over survival and progression-free survival analysis. RESULTS 62% (31/50) of astrocytomas and 16% (8/51) of oligodendrogliomas harboured pathogenic TP53 mutations. Pathogenic hotspot mutations in codon 273 (c.817 C>T and c.818 G>A) was prevalent in astrocytoma with 58% (18/31) of tumours with these mutations. TP53 mutation status was maintained between primary and recurrent tumours in 93% of cases. In astrocytoma, overall survival of TP53 mutant patients was longer compared to TP53 wild-type patients (p<0.01) but was not significant after adjusting for age, gender, grade and IDH1 mutation status. In contrast, astrocytoma patients with specific TP53 mutation in codon 273 showed significantly better survival compared to other TP53 mutant and TP53 wild-type patients combined (p<0.01) in our multivariate analysis. Time to first recurrence (progression-free survival) of TP53 mutant patients was significantly longer than TP53 wild-type patients (p<0.01) after adjustments were made, while TP53 mutation in codon 273 was not prognostic for progression-free survival. In oligodendroglioma patients, TP53 mutations did not significantly affect overall survival and progression-free survival. CONCLUSION In agreement with others, TP53 mutation is more prevalent in Astrocytoma and mutations in codon 273 are significantly associated with longer survival.

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Expression levels of miR-34-family microRNAs are associated with TP53 mutation status in head and neck squamous cell carcinoma

European Archives of Oto-Rhino-Laryngology ◽

10.1007/s00405-018-5223-x ◽

2018 ◽

Vol 276 (2) ◽

pp. 521-533 ◽

Cited By ~ 2

Author(s):

Chanatip Metheetrairut ◽

Chanticha Chotigavanich ◽

Kanchana Amornpichetkul ◽

Phawin Keskool ◽

Sunun Ongard ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Tp53 Mutation ◽

Neck Squamous Cell Carcinoma ◽

Mutation Status ◽

Expression Levels

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TP53 drives invasion through expression of its Δ133p53β variant

eLife ◽

10.7554/elife.14734 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 19

Author(s):

Gilles Gadea ◽

Nikola Arsic ◽

Kenneth Fernandes ◽

Alexandra Diot ◽

Sébastien M Joruiz ◽

...

Keyword(s):

Cancer Cell ◽

Cancer Progression ◽

Cell Invasion ◽

Tp53 Mutation ◽

P53 Protein ◽

Clinical Analysis ◽

Breast Cancer Patients ◽

Cancer Cell Invasion ◽

Mutation Status ◽

Risk Of Cancer

TP53 is conventionally thought to prevent cancer formation and progression to metastasis, while mutant TP53 has transforming activities. However, in the clinic, TP53 mutation status does not accurately predict cancer progression. Here we report, based on clinical analysis corroborated with experimental data, that the p53 isoform Δ133p53β promotes cancer cell invasion, regardless of TP53 mutation status. Δ133p53β increases risk of cancer recurrence and death in breast cancer patients. Furthermore Δ133p53β is critical to define invasiveness in a panel of breast and colon cell lines, expressing WT or mutant TP53. Endogenous mutant Δ133p53β depletion prevents invasiveness without affecting mutant full-length p53 protein expression. Mechanistically WT and mutant Δ133p53β induces EMT. Our findings provide explanations to 2 long-lasting and important clinical conundrums: how WT TP53 can promote cancer cell invasion and reciprocally why mutant TP53 gene does not systematically induce cancer progression.

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Determination of Both TP53 Mutation Status and the Amount of p53 Protein Has Limited Diagnostic Importance for Patients with Ovarian Cancer

Current Medicinal Chemistry ◽

10.2174/0929867329666220112141211 ◽

2022 ◽

Vol 29 ◽

Author(s):

Sebastian M. Klein ◽

Maria Bozko ◽

Astrid Toennießen ◽

Nisar P. Malek ◽

Przemyslaw Bozko

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Cancer Patients ◽

Tp53 Mutation ◽

P53 Protein ◽

Mutation Status ◽

Tumor Tissues ◽

Tp53 Status ◽

Diagnostic Importance

Background: Ovarian cancer is one of the most aggressive types of gynecologic cancers. Many patients have a relapse within two years after diagnosis and subsequent therapy. Among different genetic changes generally believed to be important for the development of cancer, TP53 is the most common mutation in the case of ovarian tumors. Objective: Our work aims to compare the outcomes of different comparisons based on the overall survival of ovarian cancer patients, determination of TP53 status, and amount of p53 protein in tumor tissues. Methods: We analyzed and compared a collective of 436 ovarian patient’s data. Extracted data include TP53 mutation status, p53 protein level, and information on the overall survival. Values for p53 protein level in dependence of TP53 mutation status were compared using the Independent-Samples t-Test. Survival analyses were displayed by Kaplan-Meier plots, using the log-rank test to check for statistical significance. Results: We have not found any statistically significant correlations between determination of TP53 status, amount of p53 protein in tumor tissues, and overall survival of ovarian cancer patients. Conclusion: In ovarian tumors both determination of TP53 status as well as p53 protein amount has only limited diagnostic importance.

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Recent progress of prognostic biomarkers and risk scoring systems in chronic lymphocytic leukemia

Biomarker Research ◽

10.1186/s40364-020-00222-3 ◽

2020 ◽

Vol 8 (1) ◽

Author(s):

Xiaoya Yun ◽

Ya Zhang ◽

Xin Wang

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Tp53 Mutation ◽

Scoring Systems ◽

Lymphocytic Leukemia ◽

Prognostic Biomarkers ◽

Novel Agents ◽

Prognostic Models ◽

Predictive Values ◽

Mutation Status ◽

Staging Systems

Abstract Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia with high heterogeneity in the western world. Thus, investigators identified a number of prognostic biomarkers and scoring systems to guide treatment decisions and validated them in the context of immunochemotherapy. A better understanding of prognostic biomarkers, including serum markers, flow cytometry outcomes, IGHV mutation status, microRNAs, chromosome aberrations and gene mutations, have contributed to prognosis in CLL. Del17p/ TP53 mutation, NOTCH1 mutation, CD49d, IGHV mutation status, complex karyotypes and microRNAs were reported to be of predictive values to guide clinical decisions. Based on the biomarkers above, classic prognostic models, such as the Rai and Binet staging systems, MDACC nomogram, GCLLSG model and CLL-IPI, were developed to improve risk stratification and tailor treatment intensity. Considering the presence of novel agents, many investigators validated the conventional prognostic biomarkers in the setting of novel agents and only TP53 mutation status/del 17p and CD49d expression were reported to be of prognostic value. Whether other prognostic indicators and models can be used in the context of novel agents, further studies are required.

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