Distinct p53 gene signatures are needed to predict prognosis and response to chemotherapy in ER-positive and ER-negative breast cancers
Published version of a preprint
Abstract
Purpose Estrogen receptor-positive (ER+) and -negative (ER) breast cancers are molecularly distinct diseases. We hypothesized that p53 mutations may lead to different transcriptional changes and carry different prognostic value in these two different types of cancers. Experimental design We developed a 39-gene p53 signature derived from 213 ER+ and a separate 30-gene signature from 38 ER- cancers with known mutation status and tested their prognostic and chemotherapy response predictive values in ER+ and ER- cancers, respectively. Results External validation to predict p53 status (n = 103) showed sensitivity and specificity of 89% and 54% for the 39-gene signature, and 82% and 61% for the 30-gene signature. The 39-gene signature was predictive of worse distant metastasis free survival in ER+ cancers in two separate prognostic data sets (n = 255, HR: 2.3, P = 0.005 and n = 198, HR: 2.17, P = 0.09). It also predicted for poor prognosis even with adjuvant tamoxifen therapy (n = 277, HR = 2.43, P Conclusions P53 dysfunction is prognostically most relevant in ER+ cancers and supports the hypothesis that different predictive or prognostic markers will be needed for different molecular subsets of breast cancer.
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A TP53-mutation signature reportedly predicts mutation in breast cancer accurately.
“Since a TP53-mutation signature reportedly predicts mutation in breast cancer accurately (15), we aimed to estimate CTNNB1-mutations with a mutation-signature generated in our training set.”
From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [15]
All efforts to develop and translate effective and safe Wnt-pathway modulators into the clinical setting have been complicated by the multifaceted nature of Wnt-signaling.
“However, all efforts to develop and translate effective and safe Wnt-pathway modulators into the clinical setting have been complicated by the multifaceted nature of Wnt-signaling (4, 15).”
From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [15]
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Lachenmayer, A., Alsinet, C., Savic, R., Cabellos, L., Toffanin, S., Hoshida, Y., Villanueva, A., Minguez, B., Newell, P., Tsai, H.-W., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-2322 · Cited by 306 · see citing works
Pare, R., Soon, P. S., Shah, A., & Lee, C. S. (2019) · PLOS ONE · doi:10.1371/journal.pone.0214604 · Cited by 23 · see citing works
- Authors
- Coutant, C., Rouzier, R., Qi, Y., Lehmann-Che, J., Bianchini, G., Iwamoto, T., Hortobagyi, G. N., Symmans, W. F., Uzan, S., Andre, F., de Thé, H., & Pusztai, L.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Authors' Affiliations: Departments of 1Breast Medical Oncology, 2Bioinformatics, and 3Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; 4Department of Gynecology and Obstetrics, University Pierre et Marie Curie, Paris 6 and UPRES EA 4053, Tenon Hospital, Assistance Publique des Hôpitaux de Paris; 5Department of Biochemistry and INSERM U944 University Rene Diderot, Paris 7, Saint Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris, France; 6Division of Medical Oncology, Fondazione IRCCS Istituto Tumori di Milano, Milan, Italy; 7Department of Gastroenterological Surgery and Surgical Oncology, Okayama, University Graduate School of Medicine and Dentistry, Okayama, Japan; and 8The Translational Research Unit, Institut Gustave Roussy, Villejuif, France
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2011-04-14
- Volume
- 17
- Issue
- 8
- Pages
- 2591-2601
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2118949116
- Cited by
- 64
- References
- 0
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 8 · 2022: 4 · 2021: 3 · 2020: 5 · 2019: 2 · 2018: 3 · 2017: 2 · 2016: 1 · 2015: 4 · 2014: 4 · 2013: 5 · 2012: 13
- FWCI
- 2.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fondation de France
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- TP53 mutation, gene expression signatures, estrogen receptor-positive breast cancer, estrogen receptor-negative breast cancer, prognosis, chemotherapy response prediction, distant metastasis-free survival, tamoxifen, gene expression changes, molecular subtypes
- MeSH terms
- Adult, Aged, Aged, 80 and over, Breast Neoplasms, Female, Humans, Middle Aged, Mutation, Predictive Value of Tests, Prognosis, Receptors, Estrogen, Multivariate Analysis, Survival Analysis, Tumor Suppressor Protein p53, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling
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