An Expression Signature for p53 Status in Human Breast Cancer Predicts Mutation Status, Transcriptional Effects, and Patient Survival

Perturbations of the p53 pathway are associated with more aggressive and therapeutically refractory tumors. However, molecular assessment of p53 status, by using sequence analysis and immunohistochemistry, are incomplete assessors of p53 functional effects. We posited that the transcriptional finger...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2005-09, Vol.102 (38), p.13550-13555
Main Authors: Miller, Lance D., Smeds, Johanna, George, Joshy, Vega, Vinsensius B., Vergara, Liza, Ploner, Alexander, Pawitan, Yudi, Hall, Per, Klaar, Sigrid, Liu, Edison T., Bergh, Jonas, White, Raymond L.
Format: Article
Language:English
Subjects:
Biological Sciences
Breast cancer
Breast neoplasms
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - mortality
Cancer
Datasets
Disease free survival
Female
Gene expression
Gene Expression Profiling - methods
Gene Expression Regulation, Neoplastic
Genes
Genetic mutation
Genetics
Humans
Liver cancer
Mutation
Oligonucleotide Array Sequence Analysis - methods
Predictive Value of Tests
Prognosis
Signatures
Survival analysis
Transcription, Genetic
Tumor Suppressor Protein p53 - biosynthesis
Tumor Suppressor Protein p53 - genetics
Tumors
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Summary:Perturbations of the p53 pathway are associated with more aggressive and therapeutically refractory tumors. However, molecular assessment of p53 status, by using sequence analysis and immunohistochemistry, are incomplete assessors of p53 functional effects. We posited that the transcriptional fingerprint is a more definitive downstream indicator of p53 function. Herein, we analyzed transcript profiles of 251 p53-sequenced primary breast tumors and identified a clinically embedded 32-gene expression signature that distinguishes p53-mutant and wild-type tumors of different histologies and outperforms sequence-based assessments of p53 in predicting prognosis and therapeutic response. Moreover, the p53 signature identified a subset of aggressive tumors absent of sequence mutations in p53 yet exhibiting expression characteristics consistent with p53 deficiency because of attenuated p53 transcript levels. Our results show the primary importance of p53 functional status in predicting clinical breast cancer behavior.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0506230102