Systems biology modeling of the radiation sensitivity network: a biomarker discovery platform.

PURPOSE The discovery of effective biomarkers is a fundamental goal of molecular medicine. Developing a systems-biology understanding of radiosensitivity can enhance our ability of identifying radiation-specific biomarkers. METHODS AND MATERIALS Radiosensitivity, as represented by the survival fraction at 2 Gy was modeled in 48 human cancer cell lines. We applied a linear regression algorithm that integrates gene expression with biological variables, including ras status (mut/wt), tissue of origin and p53 status (mut/wt). RESULTS The biomarker discovery platform is a network representation of the top 500 genes identified by linear regression analysis. This network was reduced to a 10-hub network that includes c-Jun, HDAC1, RELA (p65 subunit of NFKB), PKC-beta, SUMO-1, c-Abl, STAT1, AR, CDK1, and IRF1. Nine targets associated with radiosensitization drugs are linked to the network, demonstrating clinical relevance. Furthermore, the model identified four significant radiosensitivity clusters of terms and genes. Ras was a dominant variable in the analysis, as was the tissue of origin, and their interaction with gene expression but not p53. Overrepresented biological pathways differed between clusters but included DNA repair, cell cycle, apoptosis, and metabolism. The c-Jun network hub was validated using a knockdown approach in 8 human cell lines representing lung, colon, and breast cancers. CONCLUSION We have developed a novel radiation-biomarker discovery platform using a systems biology modeling approach. We believe this platform will play a central role in the integration of biology into clinical radiation oncology practice.

[1]  B. Wang,et al.  Involvement of Protein Kinase C-Related Anti-apoptosis Signaling in Radiation-Induced Apoptosis in Murine Thymic Lymphoma(3SBH5) Cells , 2004, Radiation research.

[2]  John N Weinstein,et al.  Integrating global gene expression and radiation survival parameters across the 60 cell lines of the National Cancer Institute Anticancer Drug Screen. , 2008, Cancer research.

[3]  Donald Geman,et al.  Merging microarray data from separate breast cancer studies provides a robust prognostic test , 2008, BMC Bioinformatics.

[4]  Dan Yang,et al.  NF-κB Is Required for UV-Induced JNK Activation via Induction of PKCδ , 2006 .

[5]  L J Peters,et al.  The ESTRO Regaud lecture. Inherent radiosensitivity of tumor and normal tissue cells as a predictor of human tumor response. , 1990, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[6]  P. Okunieff,et al.  Mammalian DNA topoisomerase I mediates the enhancement of radiation cytotoxicity by camptothecin derivatives. , 1997, Cancer Research.

[7]  Albert J. Fornace,et al.  Integrating global gene expression and radiation survival parameters across the 60 cell lines of the National Cancer Institute Anticancer Drug Screen (Cancer Research (January 15, 2008) 68 (415-424)) , 2008 .

[8]  R. Bristow,et al.  The p53 protein family and radiation sensitivity: Yes or no? , 2004, Cancer and Metastasis Reviews.

[9]  O. Hobert,et al.  Caenorhabditis elegans ABL-1 antagonizes p53-mediated germline apoptosis after ionizing irradiation , 2004, Nature Genetics.

[10]  K. Camphausen,et al.  Histone deacetylation as a target for radiosensitization. , 2006, Current topics in developmental biology.

[11]  Leroy Hood,et al.  The impact of systems approaches on biological problems in drug discovery , 2004, Nature Biotechnology.

[12]  David E. Misek,et al.  Gene-expression profiles predict survival of patients with lung adenocarcinoma , 2002, Nature Medicine.

[13]  F.A.M. Bordonaba,et al.  Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer , 2009 .

[14]  E. Bernhard,et al.  The influence of Ras pathway signaling on tumor radiosensitivity , 2004, Cancer and Metastasis Reviews.

[15]  S. Powell,et al.  Repair of radiation damage to DNA , 2004, British Journal of Cancer.

[16]  J. Hain,et al.  Increased G2 chromosomal radiosensitivity in cancer patients: the role of cdk1/cyclin-B activity level in the mechanisms involved. , 2000, International journal of radiation biology.

[17]  A. Hanlon,et al.  Effect of sequencing of androgen deprivation and radiotherapy on prostate cancer growth. , 2003, International journal of radiation oncology, biology, physics.

[18]  Steven Eschrich,et al.  Prediction of radiation sensitivity using a gene expression classifier. , 2005, Cancer research.

[19]  R. A. Schmiedt,et al.  Activation of Nuclear Factor κB In vivo Selectively Protects the Murine Small Intestine against Ionizing Radiation-Induced Damage , 2004, Cancer Research.

[20]  S. Friend,et al.  Cancer Biomarkers—An Invitation to the Table , 2006, Science.

[21]  G. Wani,et al.  DNA repair factor XPC is modified by SUMO-1 and ubiquitin following UV irradiation , 2005, Nucleic acids research.

[22]  A. Gudkov,et al.  The role of p53 in determining sensitivity to radiotherapy , 2003, Nature Reviews Cancer.

[23]  Michael E Phelps,et al.  Systems Biology and New Technologies Enable Predictive and Preventative Medicine , 2004, Science.

[24]  D. Hallahan,et al.  Radiation signaling mediated by Jun activation following dissociation from a cell type-specific repressor. , 1993, The Journal of biological chemistry.

[25]  K. Ang,et al.  Chemoradiotherapy: Emerging treatment improvement strategies , 2003, Head & neck.

[26]  Albert-László Barabási,et al.  Error and attack tolerance of complex networks , 2000, Nature.

[27]  Nanxin Li,et al.  Ionizing radiation and short wavelength UV activate NF-kappaB through two distinct mechanisms. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[28]  H. Kitano.  Systems Biology: A Brief Overview , 2002, Science.

[29]  B. Wouters,et al.  Apoptosis, p53, and tumor cell sensitivity to anticancer agents. , 1999, Cancer research.

[30]  I. Yang,et al.  Molecular staging for survival prediction of colorectal cancer patients. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  Hemant Ishwaran,et al.  An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer , 2008, Proceedings of the National Academy of Sciences.

[32]  R. Muschel,et al.  p34Cdc2 Kinase Activity Is Excluded from the Nucleus during the Radiation-induced G2 Arrest in HeLa Cells* , 1999, The Journal of Biological Chemistry.

[33]  D. Hallahan,et al.  Prolonged c-jun expression in irradiated ataxia telangiectasia fibroblasts. , 1996, International journal of radiation oncology, biology, physics.

[34]  W. El-Deiry.  The role of p53 in chemosensitivity and radiosensitivity , 2003, Oncogene.

[35]  B. Fertil,et al.  Distribution of radiation sensitivities for human tumor cells of specific histological types: comparison of in vitro to in vivo data. , 1986, International journal of radiation oncology, biology, physics.

[36]  Michael O. Kelleher,et al.  Regulation of the IRF-1 tumour modifier during the response to genotoxic stress involves an ATM-dependent signalling pathway , 2002, Oncogene.

[37]  C. Perou,et al.  Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. , 2004, Cancer cell.

[38]  B. Fertil,et al.  Intrinsic radiosensitivity of human cell lines is correlated with radioresponsiveness of human tumors: analysis of 101 published survival curves. , 1985, International journal of radiation oncology, biology, physics.

[39]  K. Camphausen,et al.  Gleevec-mediated inhibition of Rad51 expression and enhancement of tumor cell radiosensitivity. , 2003, Cancer research.

[40]  Channing J Der,et al.  The dark side of Ras: regulation of apoptosis , 2003, Oncogene.

[41]  A. Barabasi,et al.  Lethality and centrality in protein networks , 2001, Nature.

[42]  Yudong D. He,et al.  Gene expression profiling predicts clinical outcome of breast cancer , 2002, Nature.

[43]  J. Mesirov,et al.  Chemosensitivity prediction by transcriptional profiling , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[44]  R. Bristow,et al.  Combined-modality treatment of solid tumors using radiotherapy and molecular targeted agents. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[45]  A. Isaksson,et al.  STAT1 signaling is associated with acquired crossresistance to doxorubicin and radiation in myeloma cell lines , 2007, International journal of cancer.