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The influence of cell context on the selection pressure for p53 mutation in human cancer.

The influence of cell context on the selection pressure for p53 mutation in human cancer.
The influence of cell context on the selection pressure for p53 mutation in human cancer.
Although p53 mutation is, overall, by far the most frequent somatic genetic abnormality in human cancer, in some common tumour types, notably carcinoma of breast, it is seen only in a phenotypically-distinct sub-set of cases, often correlated with adverse prognosis. Conventionally, this is viewed as the consequence of random differences in acquired genetic events acting on a common cell. Here we develop a fundamentally different hypothesis, which proposes that the liability of a given tumour to exhibit p53 mutation is predetermined by the nature of its cell of origin and, more specifically, depends on the extent to which wild-type p53 forms a rate-limiting step in the control of proliferative lifespan in that cell. In other words, the phenotype of the cell of origin constrains both tumour phenotype and 'choice' of genetic events. This concept can be extended to tumour progression, where evidence particularly from thyroid tumorigenesis suggests that a switch in differentiation state can play a major causal role in tumour evolution by altering the selection pressure for p53 mutation. Finally, analysis of transformed thyroid cells has also revealed a novel physiological mechanism by which growth suppression by wild-type p53 may be evaded in cell types whose lifespan control is p53-independent.
0143-3334
29-36
Wynford-Thomas, D
b95cdf4a-87cc-4390-a893-eee9cc7fff5d
Blaydes, J
e957f999-fd91-4f77-ad62-5b4ef069b15b
Wynford-Thomas, D
b95cdf4a-87cc-4390-a893-eee9cc7fff5d
Blaydes, J
e957f999-fd91-4f77-ad62-5b4ef069b15b

Wynford-Thomas, D and Blaydes, J (1998) The influence of cell context on the selection pressure for p53 mutation in human cancer. Carcinogenesis, 19 (1), 29-36.

Record type: Article

Abstract

Although p53 mutation is, overall, by far the most frequent somatic genetic abnormality in human cancer, in some common tumour types, notably carcinoma of breast, it is seen only in a phenotypically-distinct sub-set of cases, often correlated with adverse prognosis. Conventionally, this is viewed as the consequence of random differences in acquired genetic events acting on a common cell. Here we develop a fundamentally different hypothesis, which proposes that the liability of a given tumour to exhibit p53 mutation is predetermined by the nature of its cell of origin and, more specifically, depends on the extent to which wild-type p53 forms a rate-limiting step in the control of proliferative lifespan in that cell. In other words, the phenotype of the cell of origin constrains both tumour phenotype and 'choice' of genetic events. This concept can be extended to tumour progression, where evidence particularly from thyroid tumorigenesis suggests that a switch in differentiation state can play a major causal role in tumour evolution by altering the selection pressure for p53 mutation. Finally, analysis of transformed thyroid cells has also revealed a novel physiological mechanism by which growth suppression by wild-type p53 may be evaded in cell types whose lifespan control is p53-independent.

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Published date: January 1998

Identifiers

Local EPrints ID: 150579
URI: http://eprints.soton.ac.uk/id/eprint/150579
ISSN: 0143-3334
PURE UUID: 36f22566-8dc2-419a-a02c-7769e270db9f
ORCID for J Blaydes: ORCID iD orcid.org/0000-0001-8525-0209

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Date deposited: 20 Jul 2010 14:08
Last modified: 23 Jul 2022 01:47

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Contributors

Author: D Wynford-Thomas
Author: J Blaydes ORCID iD

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