TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use
TL;DR: Current knowledge on TP53 gene variations observed in human cancers and populations, and current clinical applications derived from this knowledge are summarized.
Abstract: Somatic mutations in the TP53 gene are one of the most frequent alterations in human cancers, and germline mutations are the underlying cause of Li-Fraumeni syndrome, which predisposes to a wide spectrum of early-onset cancers. Most mutations are single-base substitutions distributed throughout the coding sequence. Their diverse types and positions may inform on the nature of mutagenic mechanisms involved in cancer etiology. TP53 mutations are also potential prognostic and predictive markers, as well as targets for pharmacological intervention. All mutations found in human cancers are compiled in the IARC TP53 Database (http://www-p53.iarc.fr/). A human TP53 knockin mouse model (Hupki mouse) provides an experimental model to study mutagenesis in the context of a human TP53 sequence. Here, we summarize current knowledge on TP53 gene variations observed in human cancers and populations, and current clinical applications derived from this knowledge.
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Wellcome Trust Sanger Institute1, Cambridge University Hospitals NHS Foundation Trust2, Wellcome Trust3, University of British Columbia4, University of Cambridge5, The Breast Cancer Research Foundation6, Oslo University Hospital7, University of Oslo8, University of Münster9, Université libre de Bruxelles10, German Cancer Research Center11, University of Iceland12, Erasmus University Rotterdam13, French Institute of Health and Medical Research14, Paris Descartes University15, University of Paris16, Broad Institute17, University of Bergen18, University of Queensland19, University of Oviedo20, University of Glasgow21, Harvard University22, United States Department of Veterans Affairs23, Netherlands Cancer Institute24, University of Kiel25, Radboud University Nijmegen26, King's College London27, Curie Institute28, Bankstown Lidcombe Hospital29, University of New South Wales30, University of Barcelona31
TL;DR: It is shown that hypermutation localized to small genomic regions, ‘kataegis’, is found in many cancer types, and this results reveal the diversity of mutational processes underlying the development of cancer.
Abstract: All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.
7,904 citations
Cites background from "TP53 Mutations in Human Cancers: Or..."
...Since there are six classes of base substitution C>A, C>G, C>T, T>A, T>C, T>G (all substitutions are referred to by the pyrimidine of the mutated WatsonCrick base pair) and since we incorporated information on the bases immediately 5′ and 3′ to each mutated base, there are 96 possible mutations in this classification....
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...The higher prevalence of C>A mutations on Nature....
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...There are signatures characterized predominantly by C>T (1A/B, 6, 7, 11, 15, 19), C>A (4, 8, 18), T>C (5, 12, 16, 21) and T>G mutations (9, 17), with others showing distinctive combinations of mutation classes (2, 13, 14)....
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...For example, Signature 4 shows transcriptional strand bias for C>A mutations (Fig....
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...To overcome this limitation, we examined our dataset for samples that are predominantly generated by one mutational signature (i.e., more than 50% of the somatic mutations in the sample belong to an individual mutational signature) and/or for samples in which all operative mutational processes have mutually exclusive patterns of mutations (e.g., a sample with mutations only from Signature 1B, which is predominantly C>T substitutions, and Signature 18, which is predominantly C>A substitutions)....
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Journal Article•
TL;DR: In this paper, the coding exons of the family of 518 protein kinases were sequenced in 210 cancers of diverse histological types to explore the nature of the information that will be derived from cancer genome sequencing.
Abstract: AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore
PL02-05
All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.
2,737 citations
TL;DR: TP53 is the most frequently mutated gene in human cancer and must be interpreted to understand how cell type, mutation profile, and epigenetic cell state dictate outcomes, and how might it restore its tumor-suppressive activities in cancer.
1,215 citations
Cites background from "TP53 Mutations in Human Cancers: Or..."
...In many cancers, TP53 mutation is linked to poor patient prognosis (Olivier et al., 2010)....
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TL;DR: The roles of classical p53 functions, as well as emerging p53-regulated processes, in tumour suppression are discussed.
Abstract: p53 is a crucial tumour suppressor that responds to diverse stress signals by orchestrating specific cellular responses, including transient cell cycle arrest, cellular senescence and apoptosis, which are all processes associated with tumour suppression. However, recent studies have challenged the relative importance of these canonical cellular responses for p53-mediated tumour suppression and have highlighted roles for p53 in modulating other cellular processes, including metabolism, stem cell maintenance, invasion and metastasis, as well as communication within the tumour microenvironment. In this Opinion article, we discuss the roles of classical p53 functions, as well as emerging p53-regulated processes, in tumour suppression.
1,084 citations
TL;DR: Recent studies that shed light on endogenous sources of mutation and epigenomic features that promote genomic instability during cancer evolution are reviewed.
919 citations
Cites background from "TP53 Mutations in Human Cancers: Or..."
...Indeed, C>T substitutions at CpGsmake up 25%of somatic mutations in TP53 codons, implying that mutations associated with this signature might drive tumorigenesis (Olivier et al., 2010)....
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References
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TL;DR: The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues as mentioned in this paper.
Abstract: Mutations in the evolutionarily conserved codons of the p53 tumor suppressor gene are common in diverse types of human cancer. The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues. Analysis of these mutations can provide clues to the etiology of these diverse tumors and to the function of specific regions of p53. Transitions predominate in colon, brain, and lymphoid malignancies, whereas G:C to T:A transversions are the most frequent substitutions observed in cancers of the lung and liver. Mutations at A:T base pairs are seen more frequently in esophageal carcinomas than in other solid tumors. Most transitions in colorectal carcinomas, brain tumors, leukemias, and lymphomas are at CpG dinucleotide mutational hot spots. G to T transversions in lung, breast, and esophageal carcinomas are dispersed among numerous codons. In liver tumors in persons from geographic areas in which both aflatoxin B1 and hepatitis B virus are cancer risk factors, most mutations are at one nucleotide pair of codon 249. These differences may reflect the etiological contributions of both exogenous and endogenous factors to human carcinogenesis.
8,063 citations
TL;DR: The author regrets the lack of citations for many important observations mentioned in the text, but their omission is made necessary by restrictions in the preparation of review manuscripts.
7,653 citations
TL;DR: The spontaneous decay of DNA is likely to be a major factor in mutagenesis, carcinogenesis and ageing, and also sets limits for the recovery of DNA fragments from fossils.
Abstract: Although DNA is the carrier of genetic information, it has limited chemical stability. Hydrolysis, oxidation and nonenzymatic methylation of DNA occur at significant rates in vivo, and are counteracted by specific DNA repair processes. The spontaneous decay of DNA is likely to be a major factor in mutagenesis, carcinogenesis and ageing, and also sets limits for the recovery of DNA fragments from fossils.
5,209 citations
"TP53 Mutations in Human Cancers: Or..." refers background in this paper
...However, in the natural history of human cancers, there is often no evidence for high exposure to genotoxic substances and most mutations may arise through spontaneous replication errors, endogenous pro-mutagenic states (induced by reactive oxygen species), spontaneous deamination, or other mechanisms contributing to the spontaneous decay of DNA (Lindahl 1993)....
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...…no evidence for high exposure to genotoxic substances and most mutations may arise through spontaneous replication errors, endogenous pro-mutagenic states (induced by reactive oxygen species), spontaneous deamination, or other mechanisms contributing to the spontaneous decay of DNA (Lindahl 1993)....
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TL;DR: It is found that pancreatic cancers contain an average of 63 genetic alterations, the majority of which are point mutations, which defined a core set of 12 cellular signaling pathways and processes that were each genetically altered in 67 to 100% of the tumors.
Abstract: There are currently few therapeutic options for patients with pancreatic cancer, and new insights into the pathogenesis of this lethal disease are urgently needed. Toward this end, we performed a comprehensive genetic analysis of 24 pancreatic cancers. We first determined the sequences of 23,219 transcripts, representing 20,661 protein-coding genes, in these samples. Then, we searched for homozygous deletions and amplifications in the tumor DNA by using microarrays containing probes for approximately 10(6) single-nucleotide polymorphisms. We found that pancreatic cancers contain an average of 63 genetic alterations, the majority of which are point mutations. These alterations defined a core set of 12 cellular signaling pathways and processes that were each genetically altered in 67 to 100% of the tumors. Analysis of these tumors' transcriptomes with next-generation sequencing-by-synthesis technologies provided independent evidence for the importance of these pathways and processes. Our data indicate that genetically altered core pathways and regulatory processes only become evident once the coding regions of the genome are analyzed in depth. Dysregulation of these core pathways and processes through mutation can explain the major features of pancreatic tumorigenesis.
3,721 citations
Additional excerpts
...(Stephens et al. 2005; Sjoblom et al. 2006; Greenman et al. 2007; Jones et al. 2008)....
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TL;DR: Germ line p53 mutations have been detected in all five LFS families analyzed and can now be examined in additional families with LFS, and in other cancer patients and families with clinical features that might be attributed to the mutation.
Abstract: Familial cancer syndromes have helped to define the role of tumor suppressor genes in the development of cancer. The dominantly inherited Li-Fraumeni syndrome (LFS) is of particular interest because of the diversity of childhood and adult tumors that occur in affected individuals. The rarity and high mortality of LFS precluded formal linkage analysis. The alternative approach was to select the most plausible candidate gene. The tumor suppressor gene, p53, was studied because of previous indications that this gene is inactivated in the sporadic (nonfamilial) forms of most cancers that are associated with LFS. Germ line p53 mutations have been detected in all five LFS families analyzed. These mutations do not produce amounts of mutant p53 protein expected to exert a trans-dominant loss of function effect on wild-type p53 protein. The frequency of germ line p53 mutations can now be examined in additional families with LFS, and in other cancer patients and families with clinical features that might be attributed to the mutation.
3,662 citations
"TP53 Mutations in Human Cancers: Or..." refers background in this paper
...T53 germline mutations are the underlying cause of LFS, a familial clustering of early onset tumors including sarcomas, breast cancers, brain tumors, and adrenal cortical carcinomas (Li et al. 1988; Malkin et al. 1990)....
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