Missense Mutations Located in Structural p53 DNA-Binding Motifs Are Associated With Extremely Poor Survival in Chronic Lymphocytic Leukemia

Trbušek, Martin; Šmardová, Jana; Malčíková, Jitka; Šebejová, Ludmila; Dobeš, Petr; Svitáková, Miluše; Vranová, Vladimíra; Mráz, Marek; Francová, Hana; Doubek, Michael; Brychtová, Yvona; Kuglík, Petr; Pospı́šilová, Šárka; Mayer, Jiřı́

doi:10.1200/jco.2011.34.7872

Cited by 76 publications

(53 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, frameshift or in-frame deletions were found exclusively in EGFR-mut patients. Although most studies on the prognostic role of p53 in human cancers have only dealt with wt versus mutated patients, recent reports have demonstrated the usefulness of categorizing TP53 mutations since different mutant proteins can have widely disparate biologic effects (14,17,18). Our study strongly supports this new approach: we found that only nondisruptive mutations were significantly associated with worse OS, whereas TP53 mutations as a whole did not significantly correlate with outcome.…”

Section: Discussionsupporting

confidence: 78%

“…The small numbers of patients included in some of these studies, the differences in follow-up, and the various criteria used to classify TP53 mutations have led to contradictory results. This last aspect is particularly important as the heterogeneity of TP53 mutations has been demonstrated to correlate with similarly heterogeneous clinical outcomes in other types of tumor (14,17,18).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Nondisruptive p53 Mutations Are Associated with Shorter Survival in Patients with Advanced Non–Small Cell Lung Cancer

Molina-Vila

Bertrán-Alamillo

Gasco

et al. 2014

Clinical Cancer Research

134

149

View full text Add to dashboard Cite

Purpose: TP53 mutations in early-stage non-small cell lung cancer (NSCLC) may be associated with worse survival but their prognostic role in advanced NSCLC is controversial. In addition, it remains unclear whether mutated patients represent a clinically homogeneous group.Experimental Design: We retrospectively examined TP53 mutations and outcome in a training cohort of 318 patients with stage IIIB-IV NSCLC: 125 epidermal growth factor receptor (EGFR) wild-type (wt) and 193 EGFR mutated (mut). An independent validation cohort of 64 EGFR-mut patients was subsequently analyzed. Mutations were classified as "disruptive" and "nondisruptive" according to their predicted degree of disturbance of the p53 protein structure and function.Results: In the training cohort, TP53 mutations were found in 43 of the 125 EGFR-wt patients (34.4%). Of these, 28 had nondisruptive TP53 mutations and a median overall survival (OS) of 8.5 months, compared with 15.6 months for the remaining 97 patients (P ¼ 0.003). In the EGFR-mut group, TP53 mutations were found in 50 of the 193 patients (25.9%). The OS for the 26 patients with TP53 nondisruptive mutations was 17.8 months versus 28.4 months for the remaining 167 patients (P ¼ 0.04). In the validation cohort, the 11 patients with nondisruptive TP53 mutations had a median OS of 18.1 months compared with 37.8 months for the 53 remaining patients (P ¼ 0.006). In multivariate analyses, nondisruptive TP53 mutations had an independent, significant association with a shorter OS.Conclusions: Nondisruptive mutations in the TP53 gene are an independent prognostic factor of shorter survival in advanced NSCLC.

show abstract

Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Nondisruptive p53 Mutations Are Associated with Shorter Survival in Patients with Advanced Non–Small Cell Lung Cancer

Molina-Vila

Bertrán-Alamillo

Gasco

et al. 2014

Clinical Cancer Research

134

149

View full text Add to dashboard Cite

show abstract

“…Recently, Saleem et al analyzed loss of function mutations in p53 gene in the patients of oral squamous cell carcinoma and found that AGT to ACT missense mutation in DNA binding domain may result in impaired p53 function. In chronic lymphocytic leukemia patients, missense mutations in DNA binding motif were correlated with poor survival [154,155]. p53 has been considered as a significant player of apoptosis in many studies, and there is a growing accumulation of articles revealing its role in many malignancies.…”

Section: Death Receptormentioning

confidence: 99%

Major apoptotic mechanisms and genes involved in apoptosis

et al. 2016

View full text Add to dashboard Cite

As much as the cellular viability is important for the living organisms, the elimination of unnecessary or damaged cells has the opposite necessity for the maintenance of homeostasis in tissues, organs and the whole organism. Apoptosis, a type of cell death mechanism, is controlled by the interactions between several molecules and responsible for the elimination of unwanted cells from the body. Apoptosis can be triggered by intrinsically or extrinsically through death signals from the outside of the cell. Any abnormality in apoptosis process can cause various types of diseases from cancer to auto-immune diseases. Different gene families such as caspases, inhibitor of apoptosis proteins, B cell lymphoma (Bcl)-2 family of genes, tumor necrosis factor (TNF) receptor gene superfamily, or p53 gene are involved and/or collaborate in the process of apoptosis. In this review, we discuss the basic features of apoptosis and have focused on the gene families playing critical roles, activation/inactivation mechanisms, upstream/downstream effectors, and signaling pathways in apoptosis on the basis of cancer studies. In addition, novel apoptotic players such as miRNAs and sphingolipid family members in various kind of cancer are discussed.

show abstract

“…Recent discoveries indicate that the transcriptional activity of P53 also determines important biological processes such as metabolism via regulation of tigar (6)(7)(8) and sco2 (8)(9)(10), embryonic development of cardiomyocytes through Nkx2.5 and TroponinT2 (11), and non-cell autonomous signaling in the tumor microenvironment (12), suggesting a critical role for P53 in the regulation of basic processes of human biology. Truncation (13), transactivation domain (14), DNA-binding domain (15), and tetramerization domain mutations in the p53 gene (16) impair the ability of P53 to interact with chromatin (17,18). This eventually results in the loss of P53's transcriptional activity towards downstream effector genes involved in anticancer signaling (2,13,19).…”

Section: Introductionmentioning

confidence: 99%

The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53

Madan

Parker

Bauer

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

Missense Mutations Located in Structural p53 DNA-Binding Motifs Are Associated With Extremely Poor Survival in Chronic Lymphocytic Leukemia

Abstract: The substantially worse survival and the short TTFT suggest a strong mutated p53 gain-of-function phenotype in patients with CLL with DBMs mutations. The impact of p53 DBMs mutations on prognosis and response to therapy should be analyzed in investigative clinical trials.

Cited by 76 publications

References 37 publications

Nondisruptive p53 Mutations Are Associated with Shorter Survival in Patients with Advanced Non–Small Cell Lung Cancer

Nondisruptive p53 Mutations Are Associated with Shorter Survival in Patients with Advanced Non–Small Cell Lung Cancer

Major apoptotic mechanisms and genes involved in apoptosis

The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53

Contact Info

Product

Resources

About