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A Composite Gene Expression Signature Optimizes Prediction of Colorectal Cancer Metastasis and Outcome.

ABSTRACT: 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.A total of 468 colorectal cancer tumors including all stages (I-IV) and metastatic lesions were used to develop a new prognostic score (?PC1.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.?PC1.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 ?PC1.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. ?PC1.EMT was a "best of assessed" prognostic score when compared with 10 other known prognostic signatures.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.

SUBMITTER: Schell MJ

PROVIDER: S-EPMC4802496 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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A Composite Gene Expression Signature Optimizes Prediction of Colorectal Cancer Metastasis and Outcome.

Schell Michael J MJ Yang Mingli M Missiaglia Edoardo E Delorenzi Mauro M Soneson Charlotte C Yue Binglin B Nebozhyn Michael V MV Loboda Andrey A Bloom Gregory G Yeatman Timothy J TJ

Clinical cancer research : an official journal of the American Association for Cancer Research 20151007 3

<h4>Purpose</h4>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.<h4>Experimental design</h4>A total of 468 colorectal cancer tumors including all stages (I-IV) and metastatic lesions were used to develop a new prognostic score (ΔP ...[more]

PMID: 26446941

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Project description:BackgroundLocal relapses and metastases are primary causes of death in lung cancer patients. In the present study, we aimed to develop a prognostic signature based on metastasis-associated lncRNAs in patients with lung adenocarcinoma (LUAD).MethodsFirstly, the potential metastasis-associated lncRNAs were identified by analyzing high-throughput data from The Cancer Genome Atlas (TCGA), and based on which, an lncRNA signature was constructed for prediction of relapse in LUAD patients using Cox proportional hazards regression analysis. Moreover, the prognostic performance of the lncRNA signature was evaluated using Kaplan-Meier survival analysis, time-dependent receiver operating characteristic (ROC) curve and Cox analysis, respectively. In addition, the potential metastasis-associated function of these six lncRNAs was confirmed by lncRNA over-expression or depletion and in vitro transwell assays in LUAD cells.ResultsAn lncRNA signature consisting of six most important prognostic factors (LINC01819, ZNF649-AS1, HNF4A-AS1, FAM222A-AS1, LINC02323 and LINC00672) was developed. The signature was an independent predictor for patients' relapse-free survival (RFS), which could provide higher tumor relapse prediction capability compared with the TNM staging system at three years and five years, respectively (P = 0.0209 and P = 0.0468). Furthermore, the combination of this lncRNA signature and TNM stage had better prognostic value than TNM stage alone at three and five years, respectively (P = 0.0006 and P = 0.0096). Additionally, all the lncRNAs of the signature had a regulatory role in the LUAD cell mobility.ConclusionsThis novel six-lncRNA signature had considerable prognostic value for prediction of relapse in LUAD patients.Key pointsSignificant findings of the study The unique metastasis-associated lncRNA signature was related to tumor metastasis and prognosis in LUAD patients. What this study adds This signature had considerable prognostic value for prediction of relapse in LUAD patients.

Dataset Information

A Composite Gene Expression Signature Optimizes Prediction of Colorectal Cancer Metastasis and Outcome.

Publications

A Composite Gene Expression Signature Optimizes Prediction of Colorectal Cancer Metastasis and Outcome.

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