p53 and Human Cancer: The First Ten Thousand Mutations

Hainaut, Pierre; Hollstein, Monica

doi:10.1016/s0065-230x(08)60785-x

Cited by 868 publications

(732 citation statements)

References 335 publications

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“…14 The p53 protein is inducible in response to several forms of genotoxic and nongenotoxic stress. Once activated, it controls biologic processes, including oxidative metabolism, cell cycle, aspects of DNA repair, senescence, and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Sarcomas in TP53 germline mutation carriers

Ognjanovic

Olivier

Bergemann

et al. 2011

Cancer

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200

149

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BACKGROUND: Sarcoma is the index diagnosis of Li-Fraumeni syndrome (LFS), a familial predisposition to cancer that also includes brain cancer, breast cancer, and adrenal cortical carcinoma. Germline mutations in the TP53 gene are detected in approximately 80% of families that fulfill LFS criteria and in 15% to 25% of families that fulfill criteria for Li-Fraumeni-like syndrome (LFS), a group of related syndromes with broader clinical criteria. METHODS: The authors of this report used the International Agency for Research on Cancer TP53 database to analyze the types, age at onset and mutation patterns of sarcoma in TP53 mutation carriers. Those data were compared with sarcoma types in the general population of Caucasians using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. RESULTS: Overall, sarcomas represented 25% of tumors in TP53 mutation carriers, and 95.6% occurred before age 50 years compared with 38.3% before age 50 years in the SEER data set. Sarcomas were more likely to be rhabdomyosarcoma in carriers aged <5 years (odds ratio [OR], 11.6; 95% confidence interval [CI], 6.1-21.9) and osteosarcoma in carriers at any age (aged <20 years: OR, 1.41; 95% CI, 1.02-1.94; age >20 years: OR, 4.61; 95% CI, 2.72-7.83). Early sarcoma (at age <20 years) was associated with missense mutations in exons encoding the DNA-binding domain of p53 protein. Conversely, p53 null mutations (frameshift, splice sites, nonsense) and mutations outside the DNA-binding domain were associated with leiomyosarcoma (OR, 10.1; 95% CI, 3.4-29.9), a type of sarcoma that occurred after age 20 years. CONCLUSIONS: The current results further demonstrated genotype-phenotype correlations and age-dependent variations in sarcoma types in carriers of germline TP53 mutations. Cancer 2012;118:1387-

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Section: Introductionmentioning

confidence: 99%

Sarcomas in TP53 germline mutation carriers

Ognjanovic

Olivier

Bergemann

et al. 2011

Cancer

Self Cite

200

149

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“…6,7 For this reason, it is not surprising that mutations in the p53 gene are found in greater than half of all human tumors. 8,9 Activation of p53 occurs in response to various types of stress, including DNA damage, hypoxia, and oncogenes, and results in increased levels of modified protein. Activated p53 initiates signaling pathways that lead to either cell cycle arrest or apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Viral oncoapoptosis of human tumor cells

Aubert

Blaho

2003

Gene Ther

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Many cancer cells refractory to radiation treatment and chemotherapy proliferate because of loss of intrinsic programmed cell death (apoptosis) regulation. Consequently, the resolution of these cancers are many times outside the management capabilities of conventional therapeutics. We now report that replication-defective D27 herpes simplex virus (rd D27) triggers apoptosis in three representative transformed human cell lines. Susceptibility to virus-induced cell death is dependent on the abundance and distribution of modified p53 protein in the tumor cells indicating specific targeting of the treatment. Primary human and mouse fibroblast cells that produce modified p53 are resistant to rd D27 killing but not to apoptosis induced by nonviral environmental factors. These results suggest that induction of apoptosis by nonreplicating virus is a feasible genetic therapy approach for killing human cancer cells. Our findings may have important implications in designing novel virus-based anticancer strategies in appropriate animal model systems.

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“…Key words: endometrial cancer; p53; mutation; dominant negative; survival; serous adenocarcinoma The p53 tumor suppressor gene is mutated in about 50% of all tumors, [1][2][3] and more than 19,000 different somatic mutations have been identified. 4 Mutation of the p53 gene plays a key role in the carcinogenesis and progression of many different malignancies, including endometrial cancer.…”

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confidence: 99%

Functional analysis of p53 gene and the prognostic impact of dominant‐negative p53 mutation in endometrial cancer

Sakuragi

Watari

Ebina

et al. 2005

Intl Journal of Cancer

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In addition to the loss of function, mutant p53 can possess a dominant-negative effect on wild-type p53 and may also exert gain-offunction activity. It is not clear whether the functional status of p53 mutation contributes to differences in outcome in endometrial cancer. We collected a total of 92 RNA samples of high quality from endometrial cancer tissues, and the samples were subjected to yeast functional assay and sequencing for p53 mutations. The detected mutant p53 genes were further investigated for their dominant-negative activity using a yeast-based transdominance assay. p53 mutation was found in 24 out of 92 (26.1%) tumors, of which 10 exhibited no dominant-negative activity (recessive mutation) and 14 showed dominant-negative activity. Dominant-negative p53 mutation was related to advanced stages (p 5 0.01), nonendometrioid type tumors (p 5 0.01) and grade 3 tumors (p 5 0.04). The patients with dominant-negative mutation had significantly shorter survival than patients with no mutation (p < 0.0001) and those with a recessive mutation (p 5 0.01) in the p53 gene. No difference in survival was found between the patients with tumors harboring a recessive p53 mutation and those with tumors harboring a wild-type p53. Multivariate analysis revealed that dominantnegative p53 mutation (p 5 0.019), FIGO stage (p 5 0.0037) and histologic subtype (p 5 0.014) were independently related to patient survival. Dominant-negative p53 mutation was the most important prognostic factor for stage III/IV endometrial cancer (p 5 0.0023). In conclusion, dominant-negative p53 mutation is often found in advanced stages and aggressive histologic subtypes of endometrial cancer and it is a strong predictor of survival of patients with advanced endometrial cancer. To elucidate further the role of p53 mutation in endometrial cancer, it is necessary to investigate gain-of-function activity involving dominant-negative p53 mutant proteins. ' 2005 Wiley-Liss, Inc.Key words: endometrial cancer; p53; mutation; dominant negative; survival; serous adenocarcinoma The p53 tumor suppressor gene is mutated in about 50% of all tumors, 1-3 and more than 19,000 different somatic mutations have been identified. 4 Mutation of the p53 gene plays a key role in the carcinogenesis and progression of many different malignancies, including endometrial cancer. p53 overexpression has been shown to predict patient survival in endometrial cancer. 5-7 p53 overexpression, as determined by immunohistochemistry (IHC), is a surrogate marker of missense mutation of p53 protein. Because MDM2 is a transcriptional target of p53, loss of p53 function reduces the production of MDM2. MDM2 degrades p53 protein through ubiquitination of the protein, and reduced MDM2 production will lead to an accumulation of p53 protein in the nucleus, which is detected as overexpression by IHC. 8 IHC is a convenient method for the investigation of p53 status. However, it can be affected by many factors, such as antibody used, antigen retrieval technique and subjectivity of criteria for p53 ...

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p53 and Human Cancer: The First Ten Thousand Mutations

Cited by 868 publications

References 335 publications

Sarcomas in TP53 germline mutation carriers

Sarcomas in TP53 germline mutation carriers

Viral oncoapoptosis of human tumor cells

Functional analysis of p53 gene and the prognostic impact of dominant‐negative p53 mutation in endometrial cancer

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