Disruptive mutations in TP53 associate with survival benefit in a PARPi trial in ovarian cancer

Bueno, Alejandro Martínez; Molina, Miguel Ángel; Fielding, Anitra; Bertrán-Alamillo, Jordi; Lai, Zhongwu; Hodgson, Darren; Casas, Clara Mayo de las; Rowe, Philip; Gil, M.L. Vilardell; Spencer, Stuart; Viteri, Santiago; Lobera, J.; Rosell, Rafael; Hernandez, Axel

doi:10.1093/annonc/mdx440.036

Cited by 3 publications

(4 citation statements)

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“…Poeta et al (42) proposed the distinction between "disruptive" and "non-disruptive" TP53 mutations; while disruptive mutations likely lead to a complete loss of activity of the P53 protein, non-disruptive mutants can encode proteins which retain some of the original functions. This classification was used to stratify patients with TP53 mutations in head and neck squamous cell carcinoma (42), advanced Non-Small Cell Lung Cancer (43), breast and ovarian tumors (44,45) and esophageal squamous cell carcinoma (46). However, the association between the type of TP53 mutations and prognosis was significantly variable in the different cancers.…”

Section: Impact Of Tp53 Mutations Heterogeneity In Somatic Cancersmentioning

confidence: 99%

Heterogeneity of TP53 Mutations and P53 Protein Residual Function in Cancer: Does It Matter?

et al. 2020

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The human TP53 locus, located on the short arm of chromosome 17, encodes a tumour suppressor protein which functions as a tetrameric transcription factor capable of regulating the expression of a plethora of target genes involved in cell cycle arrest, apoptosis, DNA repair, autophagy, and metabolism regulation. TP53 is the most commonly mutated gene in human cancer cells and TP53 germ-line mutations are responsible for the cancer-prone Li-Fraumeni syndrome. When mutated, the TP53 gene generally presents missense mutations, which can be distributed throughout the coding sequence, although they are found most frequently in the central DNA binding domain of the protein. TP53 mutations represent an important prognostic and predictive marker in cancer. The presence of a TP53 mutation does not necessarily imply a complete P53 inactivation; in fact, mutant P53 proteins are classified based on the effects on P53 protein function. Different models have been used to explore these never-ending facets of TP53 mutations, generating abundant experimental data on their functional impact. Here, we briefly review the studies analysing the consequences of TP53 mutations on P53 protein function and their possible implications for clinical outcome. The focus shall be on Chronic Lymphocytic Leukemia (CLL), which also has generated considerable discussion on the role of TP53 mutations for therapy decisions.

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Section: Impact Of Tp53 Mutations Heterogeneity In Somatic Cancersmentioning

confidence: 99%

Heterogeneity of TP53 Mutations and P53 Protein Residual Function in Cancer: Does It Matter?

et al. 2020

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“…Martinez Bueno et al (57) analyzed data from a phase II trial that compared olaparib [an inhibitor of poly ADP ribose polymerase (PARP)] with a placebo. The patients with TP53 mutations exhibited a statistically significant improvement in OS following the use of olaparib compared with non-carriers (18 and 7.5 months, respectively).…”

Section: Somatic Tp53 Mutationsmentioning

confidence: 99%

TP53 mutations and SNPs as prognostic and predictive factors in patients with breast cancer (Review)

Huszno

Grzybowska

2018

Oncol Lett

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Tumor protein 53 () is a tumor suppressor gene that encodes tumor protein p53. Tumor protein p53 regulates the expression of target genes in response to cellular stress. Additionally, p53 participates in the regulation of cell cycle checkpoints, DNA repair and apoptosis. Mutations in the gene are associated with numerous types of human cancer, including breast cancer, sarcomas, brain tumors and adrenal cortical carcinomas. In breast cancer, mutations are a negative prognostic factor. Tumors with mutations are more likely to be aggressive (triple-negative or human epidermal growth factor receptor 2-positive breast cancer), and resistant to chemotherapy and radiotherapy. In addition to a well-known mutation, a number of single nucleotide polymorphisms have been systematically identified and evaluated in human populations. In the present article, the role of mutations and polymorphisms in clinical practice and breast cancer treatment has been described. Additionally, the existing data on polymorphisms in breast cancer as prognostic and predictive factors have been summarized. A literature search of these topics was performed through PubMed and abstracts of the main cancer congresses in recent years.

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“…After many attempts, we classified TP53 mutations into "disruptive" or "non-disruptive" types. This classification has been used with HNSCC (18), NSCLC (8), breast cancer (16), and ovarian cancer (45). However, no research report has described this classification in ESCC.…”

Section: Discussionmentioning

confidence: 99%

“…In our study, we clearly found that non-disruptive TP53 mutation was associated with good prognosis. In ovarian cancer, disruptive TP53 mutations showed survival benefits (45). The association between TP53 non-disruptive mutation and prognosis was significantly different in various cancers and may be related to the following factors: pathological types of tumors (adenocarcinoma versus squamous cell carcinoma) (42), treatment regime (new targeted therapy versus traditional radiotherapy/ chemotherapy), and other molecular features.…”

Section: Discussionmentioning

confidence: 99%

Non-disruptive mutation in TP53 DNA-binding domain is a beneficial factor of esophageal squamous cell carcinoma

Huang¹,

Jin²,

Zhang³

et al. 2020

Ann Transl Med

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Background: TP53 is frequently altered in esophageal squamous cell carcinoma (ESCC). However, the landscape of TP53 mutation and its effects on patients remain controversial.Methods: Somatic mutations of TP53 in 161 patients with resectable ESCC were identified by nextgeneration sequencing (NGS) and verified by immunohistochemistry (IHC). Patients were stratified into seven TP53 mutations, and depending on the extent of the effect on the encoded protein, it was divided into "disruptive" and "non-disruptive" types. The association of TP53 mutation with clinicopathological properties and disease outcome was investigated.Results: TP53 mutations were discovered in 85.7% patients, of which 68.9% carried mutations in the DNA-binding domain (DBD). A total of 47.8% and 37.9% patients had disruptive and non-disruptive TP53 mutations, respectively. Most patients carried only one TP53 mutation, but 15.5% had double mutations.TP53 mutations were dominant in exons 5 to 8. Missense mutation was the most frequent (97/163, 59.5%), and the top five frequently occurring variations included R273X, Y220X, H193, H179X, and R175H.Multivariable analysis revealed non-disruptive mutation in TP53 DBD as the independent prognostic predictor for progression-free survival (PFS) and overall survival (OS). The expression of p53 positively correlated with non-disruptive mutation in DBD. Patients with high p53 protein expression showed better outcomes.Conclusions: Non-disruptive mutation in TP53 DBD serves as an independent beneficial prognostic factor of prolonged survival in resectable ESCC.

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Disruptive mutations in TP53 associate with survival benefit in a PARPi trial in ovarian cancer

Cited by 3 publications

References 0 publications

Heterogeneity of TP53 Mutations and P53 Protein Residual Function in Cancer: Does It Matter?

Heterogeneity of TP53 Mutations and P53 Protein Residual Function in Cancer: Does It Matter?

TP53 mutations and SNPs as prognostic and predictive factors in patients with breast cancer (Review)

Non-disruptive mutation in TP53 DNA-binding domain is a beneficial factor of esophageal squamous cell carcinoma

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