Frequency of longitudinal changes in TP53 mutation status from gene sequencing of serial tumor biopsies from a large cohort of cancer patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3124-3124
Author(s):  
D. Allen Allen Annis ◽  
Dean C. Pavlick ◽  
Garrett M. Frampton ◽  
Lee A. Albacker ◽  
Vojislav M. Vukovic ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Tp53 Mutation ◽  
Gene Sequencing ◽  
Large Cohort ◽  
Cancer Type ◽  
Tumor Biopsy ◽  
Assay Sensitivity ◽  
Mutation Status ◽  
Tumor Biopsies ◽  
Tp53 Status

3124 Background: The p53 pathway is one of the most important in cancer biology, with mutation of the TP53 gene that encodes the p53 tumor suppressor protein observed in ≈50% of all cancers. We evaluated the frequency of changes in TP53 mutation status in a large cohort of serial tumor biopsies. Methods: From a database of >200,000 next-generation gene sequencing results we identified 16,592 samples arising from repeat biopsies from 7840 patients (pts), average 2.12 per pt, 1007 pts with ≥3, max 11; over an interval up to 234 months (mos), average 11.0 mos. TP53 mutations with known or unknown significance in successive biopsies and changes in assignment from TP53-Wild-Type (WT) to Mutant (Mut), or Mut to WT, were evaluated vs. cancer type and time between biopsies. Results: Table: N (%) of samples vs. change in TP53 status from previous biopsy vs. mos from initial biopsy in all samples (7840 initial + 8752 successive, 46% TP53-Mut) and the three most represented cancers: non-small cell lung cancer (NSCLC, 1189 initial + 1268 successive, 60% Mut), breast (947 initial + 993 successive, 55% Mut), multiple myeloma (MM, 578 initial + 981 successive, 18% Mut). Conclusions: Changes in TP53 status were rare (<10% of samples). Differences may occur in serial biopsy samples for pathophysiological reasons, e.g., a mutant clone becoming dominant and/or heterogeneity at different tumor biopsy sites, or analytical differences in biopsy tumor content or assay sensitivity between samples. In this analysis, WT-to-Mut changes were more frequent (5.9%) than Mut-to-WT changes (3.3%), suggesting a small selection pressure for TP53 alterations later in oncogenesis and indicating that these alterations are truncal. Mut-to-WT changes are not readily explained physiologically and may suggest these infrequent changes are mostly due to sampling or analytical variability, and genuine changes in TP53 mutation status are quite rare.[Table: see text]

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

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.

scholarly journals Differentiating TP53 Mutation Status in Pancreatic Ductal Adenocarcinoma Using Multiparametric MRI-Derived Radiomics

2021 ◽  
Vol 11 ◽  
Author(s):  
Jing Gao ◽  
Xiahan Chen ◽  
Xudong Li ◽  
Fei Miao ◽  
Weihuan Fang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tp53 Mutation ◽  
Curve Analysis ◽  
Ductal Adenocarcinoma ◽  
Arterial Phase ◽  
Support Vector ◽  
Two Dimensional ◽  
Decision Curve Analysis ◽  
Mutation Status ◽  
Tp53 Status

ObjectivesThis study assessed the preoperative prediction of TP53 status based on multiparametric magnetic resonance imaging (mpMRI) radiomics extracted from two-dimensional (2D) and 3D images.Methods57 patients with pancreatic cancer who underwent preoperative MRI were included. The diagnosis and TP53 gene test were based on resections. Of the 57 patients included 37 mutated TP53 genes and the remaining 20 had wild-type TP53 genes. Two radiologists performed manual tumour segmentation on seven different MRI image acquisition sequences per patient, including multi-phase [pre-contrast, late arterial phase (ap), portal venous phase, and delayed phase] dynamic contrast enhanced (DCE) T1-weighted imaging, T2-weighted imaging (T2WI), Diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC). PyRadiomics-package was used to generate 558 two-dimensional (2D) and 994 three-dimensional (3D) image features. Models were constructed by support vector machine (SVM) for differentiating TP53 status and DX score method were used for feature selection. The evaluation of the model performance included area under the curve (AUC), accuracy, calibration curves, and decision curve analysis.ResultsThe 3D ADC-ap-DWI-T2WI model with 11 selected features yielded the best performance for differentiating TP53 status, with accuracy = 0.91 and AUC = 0.96. The model showed the good calibration. The decision curve analysis indicated that the radiomics model had clinical utility.ConclusionsA non-invasive and quantitative mpMRI-based radiomics model can accurately predict TP53 mutation status in pancreatic cancer patients and contribute to the precision treatment.

Effect of TP53 mutation status on survival in the MAGIC trial.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 71-71 ◽  
Author(s):  
Elizabeth Catherine Smyth ◽  
Sanna Hulkki Wilson ◽  
Matthew Guy Nankivell ◽  
David Gonzalez de Castro ◽  
Andrew Wotherspoon ◽  
...  
Keyword(s):  
Genomic Dna ◽  
Tp53 Mutation ◽  
Pcr Amplification ◽  
Ffpe Tissue ◽  
Degraded Dna ◽  
P Value ◽  
Sequencing Analysis ◽  
Mutation Status ◽  
Tp53 Mutations ◽  
Tp53 Status

71 Background: In oesophagogastric cancer TP53 mutation may be prognostic and/or predict for chemoresistance, however available data are conflicting. We hypothesised that TP53 status would impact on survival for patients (pts) randomised to surgery alone or perioperative ECF chemotherapy in the MRC MAGIC trial. Methods: Genomic DNA FFPE tissue sections were extracted with QIAmp DNA FFPE Tissue Kit (Qiagen, Hilden, Germany). Mutations in exons 4-9 were screened for by fluorescent PCR -amplification of genomic DNA, followed by Capillary Electrophoresis-Single Strand Conformational Analysis (CE-SSCA). Mutations were characterised by bi -directional Sanger sequencing analysis performed on an independent PCR -reaction and the sequencing results were compared to the reference sequences in the COSMIC database. TP53 status was correlated with demographics and survival. Results: TP53 results were available on 154 pts (50% of pts with available DNA). The remainder failed CE-SSCA due to degraded DNA. Pts with/without TP53 data had similar demographics and survival. TP53 mutation was detected in 51/154 (33%) samples. Exon 4, 5, 6, 7 and 8 mutations occurred in 4%, 42%, 8%, 36% and 10% of specimens with a TP53 result. Pts with TP53 mutations were more likely to have an oesophageal or junctional tumor (vs. gastric) than TP53 wild type (WT) pts (38% vs. 17% respectively p = 0.016). Survival from surgery was comparable for pts with mutant and WT TP53 tumors in both arms of the trial (See Table). P-value for interaction between treatment group and TP53 status was 0.776, indicating no interaction was present. Conclusions: In the MAGIC trial, TP53 mutation status was not prognostic, and did not predict for lack of benefit from chemotherapy. Further study is required in order to evaluate the effect of differing TP53 mutations on treatment and survival. [Table: see text]

scholarly journals Subgroup-Specific Prognostic Implications of TP53 Mutation in Medulloblastoma

2013 ◽  
Vol 31 (23) ◽  
pp. 2927-2935 ◽  
Author(s):  
Nataliya Zhukova ◽  
Vijay Ramaswamy ◽  
Marc Remke ◽  
Elke Pfaff ◽  
David J.H. Shih ◽  
...  
Keyword(s):  
Tp53 Mutation ◽  
Survival Rates ◽  
Prognostic Impact ◽  
Molecular Subgroup ◽  
Mutation Status ◽  
Tp53 Mutations ◽  
Specific Analysis ◽  
Prognostic Implications ◽  
Tp53 Status ◽  
Independent Cohort

Purpose Reports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles. Patients and Methods We determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas. Results TP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P < .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P < .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; ± SE) was 41% ± 9% and 81% ± 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P < .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% ± 9% and 97% ± 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors. Conclusion Subgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients.

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

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.

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

2018 ◽  
Vol 276 (2) ◽  
pp. 521-533 ◽  
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

scholarly journals TP53 drives invasion through expression of its Δ133p53β variant

eLife ◽  
2016 ◽  
Vol 5 ◽  
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.

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

2018 ◽  
Vol 293 (3) ◽  
pp. 737-746 ◽  
Author(s):  
Mengyao Wang ◽  
Chao Yang ◽  
Xiuqing Zhang ◽  
Xiangchun Li
Keyword(s):  
Tp53 Mutation ◽  
Human Cancer ◽  
Mutation Status

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

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.

scholarly journals Targeted-Gene Sequencing to Catch Triple Negative Breast Cancer Heterogeneity before and after Neoadjuvant Chemotherapy

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1753 ◽  
Author(s):  
Serena Di Cosimo ◽  
Valentina Appierto ◽  
Marco Silvestri ◽  
Giancarlo Pruneri ◽  
Andrea Vingiani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Primary Tumor ◽  
Triple Negative ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Gene Sequencing ◽  
Tumor Biopsy ◽  
Recurrent Mutations ◽  
Targeted Gene Sequencing

Triple negative breast cancer (TNBC) patients not attaining pathological Complete Response (pCR) after neo-adjuvant chemotherapy (NAC) have poor prognosis. We characterized 19 patients for somatic mutations in primary tumor biopsy and residual disease (RD) at surgery by 409 cancer-related gene sequencing (IonAmpliSeqTM Comprehensive Cancer Panel). A median of four (range 1–66) genes was mutated in each primary tumor biopsy, and the most common mutated gene was TP53 followed by a long tail of low frequency mutations. There were no recurrent mutations significantly associated with pCR. However, half of patients with RD had primary tumor biopsy with mutations in genes related to the immune system compared with none of those achieving pCR. Overall, the number of mutations showed a downward trend in post- as compared to pre-NAC samples. PIK3CA was the most common altered gene after NAC. The mutational profile of TNBC during treatment as inferred from patterns of mutant allele frequencies in matched pre-and post-NAC samples showed that RD harbored alterations of cell cycle progression, PI3K/Akt/mTOR, and EGFR tyrosine kinase inhibitor-resistance pathways. Our findings support the use of targeted-gene sequencing for TNBC therapeutic development, as patients without pCR may present mutations of immune-related pathways in their primary tumor biopsy, or actionable targets in the RD.

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