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TP53: an oncogene in disguise.

Soussi T, Wiman KG - Cell Death Differ. (2015)

Bottom Line: However, it is now an indisputable fact that many p53 mutants act as oncogenic proteins.In this review, we will shatter the classical and traditional image of tumor protein p53 (TP53) as a tumor suppressor gene by emphasizing its multiple oncogenic properties that make it a potential therapeutic target that should not be underestimated.Analysis of the data generated by the various cancer genome projects highlights the high frequency of TP53 mutations and reveals that several p53 hotspot mutants are the most common oncoprotein variants expressed in several types of tumors.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK) R8:04, Stockholm SE-171 76, Sweden [2] Sorbonne Universités, UPMC Univ Paris 06, Paris F-75005, France [3] INSERM, U1138, Centre de Recherche des Cordeliers, Paris, France [4] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

ABSTRACT
The standard classification used to define the various cancer genes confines tumor protein p53 (TP53) to the role of a tumor suppressor gene. However, it is now an indisputable fact that many p53 mutants act as oncogenic proteins. This statement is based on multiple arguments including the mutation signature of the TP53 gene in human cancer, the various gains-of-function (GOFs) of the different p53 mutants and the heterogeneous phenotypes developed by knock-in mouse strains modeling several human TP53 mutations. In this review, we will shatter the classical and traditional image of tumor protein p53 (TP53) as a tumor suppressor gene by emphasizing its multiple oncogenic properties that make it a potential therapeutic target that should not be underestimated. Analysis of the data generated by the various cancer genome projects highlights the high frequency of TP53 mutations and reveals that several p53 hotspot mutants are the most common oncoprotein variants expressed in several types of tumors. The use of Muller's classical definition of mutations based on quantitative and qualitative consequences on the protein product, such as 'amorph', 'hypomorph', 'hypermorph' 'neomorph' or 'antimorph', allows a more meaningful assessment of the consequences of cancer gene modifications, their potential clinical significance, and clearly demonstrates that the TP53 gene is an atypical cancer gene.

No MeSH data available.


Related in: MedlinePlus

Genes most frequently mutated in various types of cancer in the Pan-Cancer study. Only the 40 most significantly mutated genes in the Pan-Cancer study are shown on this graph. The PAN-CANCER study included glioblastoma multiforme (GBM), lymphoblastic acute myeloid leukemia (LAML), head and neck squamous carcinoma (HNSC), lung adenocarcinoma (LUAD), lung squamous carcinoma (LUSC), breast carcinoma (BRCA), kidney renal clear-cell carcinoma (KIRC), ovarian carcinoma (OV), bladder carcinoma (BLCA), colon adenocarcinoma (COAD), uterine cervical and endometrial carcinoma (UCEC) and rectal adenocarcinoma (COADREAD). Pan-cancer: integrated data with all cancer types. Data were generated by analysis of the mutations released by Kandoth et al.3
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fig2: Genes most frequently mutated in various types of cancer in the Pan-Cancer study. Only the 40 most significantly mutated genes in the Pan-Cancer study are shown on this graph. The PAN-CANCER study included glioblastoma multiforme (GBM), lymphoblastic acute myeloid leukemia (LAML), head and neck squamous carcinoma (HNSC), lung adenocarcinoma (LUAD), lung squamous carcinoma (LUSC), breast carcinoma (BRCA), kidney renal clear-cell carcinoma (KIRC), ovarian carcinoma (OV), bladder carcinoma (BLCA), colon adenocarcinoma (COAD), uterine cervical and endometrial carcinoma (UCEC) and rectal adenocarcinoma (COADREAD). Pan-cancer: integrated data with all cancer types. Data were generated by analysis of the mutations released by Kandoth et al.3

Mentions: The Cancer Genome Atlas Pan-Cancer project has released an integrated set of genomic data from 3,200 cancer patients with 12 tumor types.3, 22 The data include genomic, epigenomic, transcriptional and proteomic information. Not surprisingly, TP53 was found to be the most frequently mutated gene in this new set of data (Figure 2 and Supplementary Figure 1). This leading position for TP53 was already obvious before the various cancer genome sequencing projects were launched and it remains unchallenged today, as most novel cancer genes are either cancer-specific (IDH1 and IDH2), mutated at low frequency (FBXW7 or GATA3) or both. One of the drawbacks of using a classification based on gene mutation frequency is that it does not take into account the diversity of the different protein variants for each gene. Although KRAS mutations are restricted to a few codons, those in other genes may be scattered along the coding region, which leads to multiple protein variants and hinders potent information on mutant diversity. Using mutational data released by the Pan-Cancer project, we have been able to perform an integrated analysis focusing directly on each protein variant (Figure 3). Three PIK3CA variants (p.H1047R, p.E545K and p.E542K) were the most frequent mutants found in the 12 tumor types; they were found in 9.9% of patients, corresponding to ~300 000 cancer cases worldwide. This observation clearly supports the importance of this gene as a target for therapy.23 Mutant p53 p.R175H ranked fourth in this analysis and 6 other p53 hotspot mutants were among the 15 most frequent protein variants found in human cancer (Figure 3a). The inclusion of other common cancers such as gastric cancer or hepatocellular carcinoma with a high frequency of TP53 mutation would provide a more accurate estimate of the number of cancer cases associated with specific p53 variants. When specific cancer types are considered, p53 mutants are always among the 10 most frequent protein variants, except in kidney cancer and acute myeloid leukemia (AML; Figure 3 and Supplementary Figures 1A–G). In ovarian cancer, the high frequency of TP53 mutation (>90%) and the lack of other frequently mutated genes leads to a distribution of protein variants that includes only p53 mutants (Supplementary Figures 1A–G). This analysis clearly shows that mutant p53 are among the most frequent protein variants expressed in human cancer and, as discussed below, these individual oncogenic proteins should not be ignored as potential targets for cancer therapy. Apart from their high frequency, these mutations are also highly ubiquitous, associated with various tumor types, and, in many cases, correlated with aggressive tumor phenotypes and poor prognosis.24, 25


TP53: an oncogene in disguise.

Soussi T, Wiman KG - Cell Death Differ. (2015)

Genes most frequently mutated in various types of cancer in the Pan-Cancer study. Only the 40 most significantly mutated genes in the Pan-Cancer study are shown on this graph. The PAN-CANCER study included glioblastoma multiforme (GBM), lymphoblastic acute myeloid leukemia (LAML), head and neck squamous carcinoma (HNSC), lung adenocarcinoma (LUAD), lung squamous carcinoma (LUSC), breast carcinoma (BRCA), kidney renal clear-cell carcinoma (KIRC), ovarian carcinoma (OV), bladder carcinoma (BLCA), colon adenocarcinoma (COAD), uterine cervical and endometrial carcinoma (UCEC) and rectal adenocarcinoma (COADREAD). Pan-cancer: integrated data with all cancer types. Data were generated by analysis of the mutations released by Kandoth et al.3
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4495363&req=5

fig2: Genes most frequently mutated in various types of cancer in the Pan-Cancer study. Only the 40 most significantly mutated genes in the Pan-Cancer study are shown on this graph. The PAN-CANCER study included glioblastoma multiforme (GBM), lymphoblastic acute myeloid leukemia (LAML), head and neck squamous carcinoma (HNSC), lung adenocarcinoma (LUAD), lung squamous carcinoma (LUSC), breast carcinoma (BRCA), kidney renal clear-cell carcinoma (KIRC), ovarian carcinoma (OV), bladder carcinoma (BLCA), colon adenocarcinoma (COAD), uterine cervical and endometrial carcinoma (UCEC) and rectal adenocarcinoma (COADREAD). Pan-cancer: integrated data with all cancer types. Data were generated by analysis of the mutations released by Kandoth et al.3
Mentions: The Cancer Genome Atlas Pan-Cancer project has released an integrated set of genomic data from 3,200 cancer patients with 12 tumor types.3, 22 The data include genomic, epigenomic, transcriptional and proteomic information. Not surprisingly, TP53 was found to be the most frequently mutated gene in this new set of data (Figure 2 and Supplementary Figure 1). This leading position for TP53 was already obvious before the various cancer genome sequencing projects were launched and it remains unchallenged today, as most novel cancer genes are either cancer-specific (IDH1 and IDH2), mutated at low frequency (FBXW7 or GATA3) or both. One of the drawbacks of using a classification based on gene mutation frequency is that it does not take into account the diversity of the different protein variants for each gene. Although KRAS mutations are restricted to a few codons, those in other genes may be scattered along the coding region, which leads to multiple protein variants and hinders potent information on mutant diversity. Using mutational data released by the Pan-Cancer project, we have been able to perform an integrated analysis focusing directly on each protein variant (Figure 3). Three PIK3CA variants (p.H1047R, p.E545K and p.E542K) were the most frequent mutants found in the 12 tumor types; they were found in 9.9% of patients, corresponding to ~300 000 cancer cases worldwide. This observation clearly supports the importance of this gene as a target for therapy.23 Mutant p53 p.R175H ranked fourth in this analysis and 6 other p53 hotspot mutants were among the 15 most frequent protein variants found in human cancer (Figure 3a). The inclusion of other common cancers such as gastric cancer or hepatocellular carcinoma with a high frequency of TP53 mutation would provide a more accurate estimate of the number of cancer cases associated with specific p53 variants. When specific cancer types are considered, p53 mutants are always among the 10 most frequent protein variants, except in kidney cancer and acute myeloid leukemia (AML; Figure 3 and Supplementary Figures 1A–G). In ovarian cancer, the high frequency of TP53 mutation (>90%) and the lack of other frequently mutated genes leads to a distribution of protein variants that includes only p53 mutants (Supplementary Figures 1A–G). This analysis clearly shows that mutant p53 are among the most frequent protein variants expressed in human cancer and, as discussed below, these individual oncogenic proteins should not be ignored as potential targets for cancer therapy. Apart from their high frequency, these mutations are also highly ubiquitous, associated with various tumor types, and, in many cases, correlated with aggressive tumor phenotypes and poor prognosis.24, 25

Bottom Line: However, it is now an indisputable fact that many p53 mutants act as oncogenic proteins.In this review, we will shatter the classical and traditional image of tumor protein p53 (TP53) as a tumor suppressor gene by emphasizing its multiple oncogenic properties that make it a potential therapeutic target that should not be underestimated.Analysis of the data generated by the various cancer genome projects highlights the high frequency of TP53 mutations and reveals that several p53 hotspot mutants are the most common oncoprotein variants expressed in several types of tumors.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK) R8:04, Stockholm SE-171 76, Sweden [2] Sorbonne Universités, UPMC Univ Paris 06, Paris F-75005, France [3] INSERM, U1138, Centre de Recherche des Cordeliers, Paris, France [4] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

ABSTRACT
The standard classification used to define the various cancer genes confines tumor protein p53 (TP53) to the role of a tumor suppressor gene. However, it is now an indisputable fact that many p53 mutants act as oncogenic proteins. This statement is based on multiple arguments including the mutation signature of the TP53 gene in human cancer, the various gains-of-function (GOFs) of the different p53 mutants and the heterogeneous phenotypes developed by knock-in mouse strains modeling several human TP53 mutations. In this review, we will shatter the classical and traditional image of tumor protein p53 (TP53) as a tumor suppressor gene by emphasizing its multiple oncogenic properties that make it a potential therapeutic target that should not be underestimated. Analysis of the data generated by the various cancer genome projects highlights the high frequency of TP53 mutations and reveals that several p53 hotspot mutants are the most common oncoprotein variants expressed in several types of tumors. The use of Muller's classical definition of mutations based on quantitative and qualitative consequences on the protein product, such as 'amorph', 'hypomorph', 'hypermorph' 'neomorph' or 'antimorph', allows a more meaningful assessment of the consequences of cancer gene modifications, their potential clinical significance, and clearly demonstrates that the TP53 gene is an atypical cancer gene.

No MeSH data available.


Related in: MedlinePlus