p53 in the Clinics

Hainaut, Pierre; Olivier, Magalí; Wiman, Klas G.

doi:10.1007/978-1-4614-3676-8

2013

DOI: 10.1007/978-1-4614-3676-8

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p53 in the Clinics

Pierre Hainaut¹,

Magalí Olivier²,

Klas G. Wiman³

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Cited by 3 publications

References 747 publications

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Interaction between p53 Mutation and a Somatic HDMX Biomarker Better Defines Metastatic Potential in Breast Cancer

Grawenda¹,

Møller²,

Lam³

et al. 2015

Cancer Research

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TP53 gene mutation is associated with poor prognosis in breast cancer, but additional biomarkers that can further refine the impact of the p53 pathway are needed to achieve clinical utility. In this study, we evaluated a role for the HDMX-S/FL ratio as one such biomarker, based on its association with other suppressor mutations that confer worse prognosis in sarcomas, another type of cancer that is surveilled by p53. We found that HDMX-S/FL ratio interacted with p53 mutational status to significantly improve prognostic capability in patients with breast cancer. This biomarker pair offered prognostic utility that was comparable with a microarray-based prognostic assay. Unexpectedly, the utility tracked independently of DNA-damaging treatments and instead with different tumor metastasis potential. Finally, we obtained evidence that this biomarker pair might identify patients who could benefit from anti-HDM2 strategies to impede metastatic progression. Taken together, our work offers a p53 pathway marker, which both refines our understanding of the impact of p53 activity on prognosis and harbors potential utility as a clinical tool. Cancer Res; 75(4); 698-708. Ó2015 AACR.

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Interaction between p53 Mutation and a Somatic HDMX Biomarker Better Defines Metastatic Potential in Breast Cancer

Grawenda¹,

Møller²,

Lam³

et al. 2015

Cancer Research

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p53 Isoforms and Their Implications in Cancer

Vieler

Sanyal

2018

Cancers

105

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In this review we focus on the major isoforms of the tumor-suppressor protein p53, dysfunction of which often leads to cancer. Mutations of the TP53 gene, particularly in the DNA binding domain, have been regarded as the main cause for p53 inactivation. However, recent reports demonstrating abundance of p53 isoforms, especially the N-terminally truncated ones, in the cancerous tissues suggest their involvement in carcinogenesis. These isoforms are ∆40p53, ∆133p53, and ∆160p53 (the names indicate their respective N-terminal truncation). Due to the lack of structural and functional characterizations the modes of action of the p53 isoforms are still unclear. Owing to the deletions in the functional domains, these isoforms can either be defective in DNA binding or more susceptive to altered ‘responsive elements’ than p53. Furthermore, they may exert a ‘dominant negative effect’ or induce more aggressive cancer by the ‘gain of function’. One possible mechanism of p53 inactivation can be through tetramerization with the ∆133p53 and ∆160p53 isoforms—both lacking part of the DNA binding domain. A recent report and unpublished data from our laboratory also suggest that these isoforms may inactivate p53 by fast aggregation—possibly due to ectopic overexpression. We further discuss the evolutionary significance of the p53 isoforms.

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p53 Immunohistochemistry and Mutation Types Mismatching in High-Grade Serous Ovarian Cancer

et al. 2022

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High-grade serous carcinoma (HGSCa) of the ovary is featured by TP53 gene mutation. Missense or nonsense mutation types accompany most cases of HGSCa that correlate well with immunohistochemical (IHC) staining results—an all (missense) or none (nonsense) pattern. However, some IHCs produce subclonal or mosaic patterns from which TP53 mutation types, including the wild type of the gene, cannot be clearly deduced. We analyzed a total of 236 cases of ovarian HGSCa and tumors of other histology by matching the results of p53 IHC staining and targeted next-generation sequencing (TruSight Tumor 170 panel). Ambiguous IHCs that do not belong to the conventional “all or none” groups were reviewed to distinguish the true wild type (WT) from potentially pathogenic subclonal or mosaic patterns. There were about 9% of sequencing-IHC mismatching cases, which were enriched by the p53 c-terminal encoding nuclear localization signal and oligomerization domain, in which the subcellular locations of p53 protein were affected. Indeed, mutations in the oligomerization domain of the p53 protein frequently revealed an unmatched signal or cytosolic staining (L289Ffs*57 (Ins), and R342*). We conclude that both mutation types and IHC patterns of p53 are important sources of information to provide a precise diagnosis of HGSCa.

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p53 in the Clinics

Cited by 3 publications

References 747 publications

Interaction between p53 Mutation and a Somatic HDMX Biomarker Better Defines Metastatic Potential in Breast Cancer

Interaction between p53 Mutation and a Somatic HDMX Biomarker Better Defines Metastatic Potential in Breast Cancer

p53 Isoforms and Their Implications in Cancer

p53 Immunohistochemistry and Mutation Types Mismatching in High-Grade Serous Ovarian Cancer

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