Abstract
Despite controversy on the correlation between p53 accumulation and TP53 mutational status, ihas long been used as a surrogate method for mutation analysis. The aim of our study was to characterise the IHC expression features of TP53 somatic mutations and define their occurrence in human cancers. A large-scale database analysis was conducted in the IARC TP53 Database (R17); 7878 mutations with IHC features were retrieved representing 60 distinct tumour sites. The majority of the alterations were immunopositive (p <0.001). Sex was known for 4897 mutations showing a female dominance (57.2%) and females carrying negative mutations were significantly younger. TP53 mutations were divided into three IHC groups according to mutation frequency and IHC positivity. Each group had female dominance. Among the IHC groups, significant correlations were observed with age at diagnosis in breast, bladder, liver, haematopoietic system and head & neck cancers. An increased likelihood of false negative IHC associated with rare nonsense mutations was observed in certain tumour sites. Our study demonstrates that p53 immunopositivity largely correlates with TP53 mutational status but expression is absent in certain mutation types.Besides, describing the complex IHC expression of TP53 somatic mutations, our results reveal some caveats for the diagnostic practice.
Highlights
The TP53 gene (17p13) encodes a nuclear transcription factor expressed in response to various stress signals such as DNA damage, heat shock, hypoxia, and oncogene overexpression
P53 IHC data was available in 7878 mutations, representing 26.5% of the 29711 TP53 somatic mutations in the International Agency for Research on Cancer (IARC) Database
A key purpose of this study was to provide a complex characterisation of IHC patterns of TP53 mutations
Summary
The TP53 gene (17p13) encodes a nuclear transcription factor expressed in response to various stress signals such as DNA damage, heat shock, hypoxia, and oncogene overexpression. The 393-amino-acid tumour-suppressor protein consists of an N-terminal transactivation domain (residues 1-42), a proline-rich domain (residues 40-92), a sequence specific core DNA binding domain (residues 103-306), a tetramerization domain (residues 307-355) and a C-terminal regulatory domain (residues 356-393) [2]. While other tumour suppressor genes are inactivated by mutations leading to absence of protein, TP53 alterations are usually missense producing stable fulllength protein [3]. Extensive efforts have been made to study TP53 mutation effect on prognosis, therapeutic response and its role in cancer diagnosis. It was previously reported, that p53 overexpression is a prognostic indicator in colorectal, lung, prostate, and breast carcinomas [5,6,7]
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