A Gene Expression Signature for Chemoradiosensitivity of Colorectal Cancer Cells

Journal Article · Mon Nov 15 00:00:00 EST 2010 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/j.ijrobp.2010.06.023· OSTI ID:21438056

Spitzner, Melanie; Emons, Georg ^[1]; Kramer, Frank ^[2]; Gaedcke, Jochen ^[1]; Rave-Fraenk, Margret ^[3]; Scharf, Jens-Gerd ^[4]; Burfeind, Peter ^[5]; Becker, Heinz ^[1]; Beissbarth, Tim ^[2]; Ghadimi, B Michael ^[1]; Ried, Thomas ^[6]; Grade, Marian ^[1]

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1. Department of General and Visceral Surgery, Georg-August-University, Goettingen (Germany)
2. Department of Medical Statistics, Georg-August-University, Goettingen (Germany)
3. Department of Radiotherapy and Radio oncology, Georg-August-University, Goettingen (Germany)
4. Department of Gastroenterology and Endocrinology, Georg-August-University, Goettingen (Germany)
5. Institute of Human Genetics, Georg-August-University, Goettingen (Germany)
6. Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States)

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 {mu}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.

• OSTI ID: 21438056
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Vol. 78, Issue 4; Other Information: DOI: 10.1016/j.ijrobp.2010.06.023; PII: S0360-3016(10)00872-2; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
CELL CYCLE
COMBINED THERAPY
GENES
NEOPLASMS
POLYMERASE CHAIN REACTION
RADIOSENSITIVITY
RECTUM
URACILS
AZINES
BODY
DIGESTIVE SYSTEM
DISEASES
GASTROINTESTINAL TRACT
GENE AMPLIFICATION
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
INTESTINES
LARGE INTESTINE
MEDICINE
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PYRIMIDINES
SENSITIVITY
THERAPY