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A Composite Gene Expression Signature Optimizes Prediction of Colorectal Cancer Metastasis and Outcome
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Abstract
Purpose: We previously found that an epithelial-to-mesenchymal transition (EMT)–based gene expression signature was highly correlated with the first principal component (PC1) of 326 colorectal cancer tumors and was prognostic. This study was designed to improve these signatures for better prediction of metastasis and outcome. Experimental Design: A total of 468 colorectal cancer tumors including all stages (I–IV) and metastatic lesions were used to develop a new prognostic score (ΔPC1.EMT) by subtracting the EMT signature score from its correlated PC1 signature score. The score was validated on six other independent datasets with a total of 3,697 tumors. Results: ΔPC1.EMT was found to be far more predictive of metastasis and outcome than its parent scores. It performed well in stages I to III, among microsatellite instability subtypes, and across multiple mutation-based subclasses, demonstrating a refined capacity to predict distant metastatic potential even in tumors with a “good” prognosis. For example, in the PETACC-3 clinical trial dataset, it predicted worse overall survival in an adjusted multivariable model for stage III patients (HR standardized by interquartile range [IQR] = 1.50; 95% confidence interval, 1.25–1.81; P = 0.000016, N = 644). The improved performance of ΔPC1.EMT was related to its propensity to identify epithelial-like subpopulations as well as mesenchymal-like subpopulations. Biologically, the signature was correlated positively with RAS signaling but negatively with mitochondrial metabolism. ΔPC1.EMT was a “best of assessed” prognostic score when compared with 10 other known prognostic signatures. Conclusions: The study developed a prognostic signature score with a propensity to detect non-EMT features, including epithelial cancer stem cell–related properties, thereby improving its potential to predict metastasis and poorer outcome in stage I–III patients. Clin Cancer Res; 22(3); 734–45. ©2015 AACR.
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“CRC tumors with activated RAS/RAF pathway appear to be associated with poor outcomes [4].”
From An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy (2022) · cites this paper as [4]
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Metadata
- Authors
- Schell, M. J., Yang, M., Missiaglia, E., Delorenzi, M., Soneson, C., Yue, B., Nebozhyn, M. V., Loboda, A., Bloom, G., & Yeatman, T. J.
- Affiliations
- Moffitt Cancer Center (US)
- 2Gibbs Cancer Center & Research Institute, Spartanburg, South Carolina.
- SIB Swiss Institute of Bioinformatics (CH)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Corresponding author
- Schell, Michael J.
- Yeatman, Timothy J.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2016-01-31
- Volume
- 22
- Issue
- 3
- Pages
- 734-745
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC4802496
- OpenAlex
- W2188527201
- Cited by
- 42
- References
- 45
- Citations by year
- 2026: 1 · 2025: 6 · 2023: 1 · 2022: 7 · 2021: 4 · 2020: 7 · 2019: 4 · 2018: 2 · 2017: 7 · 2016: 3
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Cancer Institute (U01CA157960, P30CA076292)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
- Keywords
- colorectal cancer, epithelial-mesenchymal transition, gene expression signatures, metastasis prediction, prognostic score, principal component analysis, cancer stem cells, Ras signaling, mitochondrial metabolism, microsatellite instability, stage III colorectal cancer, overall survival
- MeSH terms
- Female, Humans, Male, Neoplasm Metastasis, Neoplasm Staging, Prognosis, Colorectal Neoplasms, Reproducibility of Results, Gene Expression Regulation, Neoplastic, Cluster Analysis, Proportional Hazards Models, Gene Expression Profiling, Kaplan-Meier Estimate, Microsatellite Instability, Epithelial-Mesenchymal Transition, Transcriptome, Patient Outcome Assessment
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