Differential Gain-of-Function Activity of Three p53 Hotspot Mutants <i>In Vivo</i>

Xiong, Shunbin; Chachad, Dhruv; Zhang, Yun; Gencel-Augusto, Jovanka; Sirito, Mario; Pant, Vinod; Yang, Peirong; Sun, Chang; Chau, Gilda; Qi, Yuan; Su, Xiaoping; Whitley, Elizabeth M.; El‐Naggar, Adel K.; Lozano, Guillermina

doi:10.1158/0008-5472.can-21-3376

Cited by 22 publications

(16 citation statements)

References 35 publications

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“…These two clusters were not characterized by the differences in histological type, developmental origin, TP53 genotype proportion, the proportion of hotspot mutations. There have been several reports on the relationship between the type of GOF and the tumor spectrum in which they occur 46 , 47 . The results of the present study were consistent with previous reports, with a higher percentage of GOF with hotspot mutations, R249 in LIHC 48 , 49 and R273 in LGG 50 , 51 .…”

Section: Discussionmentioning

confidence: 99%

Different impacts of TP53 mutations on cell cycle-related gene expression among cancer types

Sasaki

Takahashi

Ouchi

et al. 2023

Sci Rep

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Functional properties caused by TP53 mutations are involved in cancer development and progression. Although most of the mutations lose normal p53 functions, some of them, gain-of-function (GOF) mutations, exhibiting novel oncogenic functions. No reports have analyzed the impact of TP53 mutations on the gene expression profile of the p53 signaling pathway across cancer types. This study is a cross-cancer type analysis of the effects of TP53 mutations on gene expression. A hierarchical cluster analysis of the expression profile of the p53 signaling pathway classified 21 cancer types into two clusters (A1 and A2). Changes in the expression of cell cycle-related genes and MKI67 by TP53 mutations were greater in cluster A1 than in cluster A2. There was no distinct difference in the effects between GOF and non-GOF mutations on the gene expression profile of the p53 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Different impacts of TP53 mutations on cell cycle-related gene expression among cancer types

Sasaki

Takahashi

Ouchi

et al. 2023

Sci Rep

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“…A portion of these are hotspot missense mutations. Their pathogenetic significance is not fully understood, but reports from other tumour types suggest that such single nucleotide variants constitute gain-of-function or separationof-function mutations [9][10][11][12][13][14][15]. The latter implies that while the tumour suppressor activity of wild-type TP53 is lost, mutant p53 reactivates parts of the TP53 pathway that are important for cancer cell survival and proliferation.…”

Section: Introductionmentioning

confidence: 99%

Disruption of the TP53 locus in osteosarcoma leads to TP53 promoter gene fusions and restoration of parts of the TP53 signalling pathway

Saba,

Difilippo,

Kovac

et al. 2023

The Journal of Pathology

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TP53 is the most frequently mutated gene in human cancer. This gene shows not only loss‐of‐function mutations but also recurrent missense mutations with gain‐of‐function activity. We have studied the primary bone malignancy osteosarcoma, which harbours one of the most rearranged genomes of all cancers. This is odd since it primarily affects children and adolescents who have not lived the long life thought necessary to accumulate massive numbers of mutations. In osteosarcoma, TP53 is often disrupted by structural variants. Here, we show through combined whole‐genome and transcriptome analyses of 148 osteosarcomas that TP53 structural variants commonly result in loss of coding parts of the gene while simultaneously preserving and relocating the promoter region. The transferred TP53 promoter region is fused to genes previously implicated in cancer development. Paradoxically, these erroneously upregulated genes are significantly associated with the TP53 signalling pathway itself. This suggests that while the classical tumour suppressor activities of TP53 are lost, certain parts of the TP53 signalling pathway that are necessary for cancer cell survival and proliferation are retained. In line with this, our data suggest that transposition of the TP53 promoter is an early event that allows for a new normal state of genome‐wide rearrangements in osteosarcoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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“…Numerous experimental studies including systematic screens of synthetically generated variant libraries [ 9 ] reported distinct functional impact of different TP53 mutation types including LOF, DN impact, and GOF [ 47 ]. Furthermore, studies of TP53 germline mutations in animal models and cohorts of Li-Fraumeni syndrome patients revealed earlier cancer onset for specific TP53 mutations [ 47 – 50 ]. By contrast, in the current study in a large pan-cancer cohort of human tumors, virtually no significant gene expression changes between different TP53 mutation types were detected.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Homogenous TP53mut-associated tumor biology across mutation and cancer types revealed by transcriptome analysis

et al. 2023

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TP53 is the most frequently mutated gene in human cancer. While no TP53-targeting drugs have been approved in the USA or Europe so far, preclinical and clinical studies are underway to investigate targeting of specific or all TP53 mutations, for example, by restoration of the functionality of mutated TP53 (TP53mut) or protecting wildtype TP53 (TP53wt) from negative regulation. We performed a comprehensive mRNA expression analysis in 24 cancer types of TCGA to extract (i) a consensus expression signature shared across TP53 mutation types and cancer types, (ii) differential gene expression patterns between tumors harboring different TP53 mutation types such as loss of function, gain of function or dominant-negative mutations, and (iii) cancer-type-specific patterns of gene expression and immune infiltration. Analysis of mutational hotspots revealed both similarities across cancer types and cancer type-specific hotspots. Underlying ubiquitous and cancer type-specific mutational processes with the associated mutational signatures contributed to explaining this observation. Virtually no genes were differentially expressed between tumors harboring different TP53 mutation types, while hundreds of genes were over- and underexpressed in TP53mut compared to TP53wt tumors. A consensus list included 178 genes that were overexpressed and 32 genes that were underexpressed in the TP53mut tumors of at least 16 of the investigated 24 cancer types. In an association analysis of immune infiltration with TP53 mutations in 32 cancer subtypes, decreased immune infiltration was observed in six subtypes, increased infiltration in two subtypes, a mixed pattern of decreased and increased immune cell populations in four subtypes, while immune infiltration was not associated with TP53 status in 20 subtypes. The analysis of a large cohort of human tumors complements results from experimental studies and supports the view that TP53 mutations should be further evaluated as predictive markers for immunotherapy and targeted therapies.

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Differential Gain-of-Function Activity of Three p53 Hotspot Mutants In Vivo

Cited by 22 publications

References 35 publications

Different impacts of TP53 mutations on cell cycle-related gene expression among cancer types

Different impacts of TP53 mutations on cell cycle-related gene expression among cancer types

Disruption of the TP53 locus in osteosarcoma leads to TP53 promoter gene fusions and restoration of parts of the TP53 signalling pathway

Homogenous TP53mut-associated tumor biology across mutation and cancer types revealed by transcriptome analysis

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