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A gene expression signature for chemoradiosensitivity of colorectal cancer cells.

ABSTRACT: PURPOSE:The standard treatment of patients with locally advanced rectal cancers comprises preoperative 5-fluorouracil-based chemoradiotherapy followed by standardized surgery. However, tumor response to multimodal treatment has varied greatly, ranging from complete resistance to complete pathologic regression. The prediction of the response is, therefore, an important clinical need. METHODS AND MATERIALS:To establish in vitro models for studying the molecular basis of this heterogeneous tumor response, we exposed 12 colorectal cancer cell lines to 3 ?M of 5-fluorouracil and 2 Gy of radiation. The differences in treatment sensitivity were then correlated with the pretherapeutic gene expression profiles of these cell lines. RESULTS:We observed a heterogeneous response, with surviving fractions ranging from 0.28 to 0.81, closely recapitulating clinical reality. Using a linear model analysis, we identified 4,796 features whose expression levels correlated significantly with the sensitivity to chemoradiotherapy (Q <.05), including many genes involved in the mitogen-activated protein kinase signaling pathway or cell cycle genes. These data have suggested a potential relevance of the insulin and Wnt signaling pathways for treatment response, and we identified STAT3, RASSF1, DOK3, and ERBB2 as potential therapeutic targets. The microarray measurements were independently validated for a subset of these genes using real-time polymerase chain reactions. CONCLUSION:We are the first to report a gene expression signature for the in vitro chemoradiosensitivity of colorectal cancer cells. We anticipate that this analysis will unveil molecular biomarkers predictive of the response of rectal cancers to chemoradiotherapy and enable the identification of genes that could serve as targets to sensitize a priori resistant primary tumors.

SUBMITTER: Spitzner M

PROVIDER: S-EPMC7339824 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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A gene expression signature for chemoradiosensitivity of colorectal cancer cells.

Spitzner Melanie M Emons Georg G Kramer Frank F Gaedcke Jochen J Rave-Fränk Margret M Scharf Jens-Gerd JG Burfeind Peter P Becker Heinz H Beissbarth Tim T Ghadimi B Michael BM Ried Thomas T Grade Marian M

International journal of radiation oncology, biology, physics 20101101 4

<h4>Purpose</h4>The standard treatment of patients with locally advanced rectal cancers comprises preoperative 5-fluorouracil-based chemoradiotherapy followed by standardized surgery. However, tumor response to multimodal treatment has varied greatly, ranging from complete resistance to complete pathologic regression. The prediction of the response is, therefore, an important clinical need.<h4>Methods and materials</h4>To establish in vitro models for studying the molecular basis of this heterog ...[more]

PMID: 20970032

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Project description:BackgroundSeveral studies have reported gene expression signatures that predict recurrence risk in stage II and III colorectal cancer (CRC) patients with minimal gene membership overlap and undefined biological relevance. The goal of this study was to investigate biological themes underlying these signatures, to infer genes of potential mechanistic importance to the CRC recurrence phenotype and to test whether accurate prognostic models can be developed using mechanistically important genes.Methods and findingsWe investigated eight published CRC gene expression signatures and found no functional convergence in Gene Ontology enrichment analysis. Using a random walk-based approach, we integrated these signatures and publicly available somatic mutation data on a protein-protein interaction network and inferred 487 genes that were plausible candidate molecular underpinnings for the CRC recurrence phenotype. We named the list of 487 genes a NEM signature because it integrated information from Network, Expression, and Mutation. The signature showed significant enrichment in four biological processes closely related to cancer pathophysiology and provided good coverage of known oncogenes, tumor suppressors, and CRC-related signaling pathways. A NEM signature-based Survival Support Vector Machine prognostic model was trained using a microarray gene expression dataset and tested on an independent dataset. The model-based scores showed a 75.7% concordance with the real survival data and separated patients into two groups with significantly different relapse-free survival (p?=?0.002). Similar results were obtained with reversed training and testing datasets (p?=?0.007). Furthermore, adjuvant chemotherapy was significantly associated with prolonged survival of the high-risk patients (p?=?0.006), but not beneficial to the low-risk patients (p?=?0.491).ConclusionsThe NEM signature not only reflects CRC biology but also informs patient prognosis and treatment response. Thus, the network-based data integration method provides a convergence between biological relevance and clinical usefulness in gene signature development.

Dataset Information

A gene expression signature for chemoradiosensitivity of colorectal cancer cells.

Publications

A gene expression signature for chemoradiosensitivity of colorectal cancer cells.

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