title: Prediction of radiation sensitivity using a gene expression classifier.
abstract: The development of a successful radiation sensitivity predictive assay has been a major goal of radiation biology for several decades. We have developed a radiation classifier that predicts the inherent radiosensitivity of tumor cell lines as measured by survival fraction at 2 Gy (SF2), based on gene expression profiles obtained from the literature. Our classifier correctly predicts the SF2 value in 22 of 35 cell lines from the National Cancer Institute panel of 60, a result significantly different from chance (P = 0.0002). In our approach, we treat radiation sensitivity as a continuous variable, significance analysis of microarrays is used for gene selection, and a multivariate linear regression model is used for radiosensitivity prediction. The gene selection step identified three novel genes (RbAp48, RGS19, and R5PIA) of which expression values are correlated with radiation sensitivity. Gene expression was confirmed by quantitative real-time PCR. To biologically validate our classifier, we transfected RbAp48 into three cancer cell lines (HS-578T, MALME-3M, and MDA-MB-231). RbAp48 overexpression induced radiosensitization (1.5- to 2-fold) when compared with mock-transfected cell lines. Furthermore, we show that HS-578T-RbAp48 overexpressors have a higher proportion of cells in G2-M (27% versus 5%), the radiosensitive phase of the cell cycle. Finally, RbAp48 overexpression is correlated with dephosphorylation of Akt, suggesting that RbAp48 may be exerting its effect by antagonizing the Ras pathway. The implications of our findings are significant. We establish that radiation sensitivity can be predicted based on gene expression profiles and we introduce a genomic approach to the identification of novel molecular markers of radiation sensitivity.
authors.affiliation: Department of Interdisciplinary Oncology, University of South Florida College of Medicine and H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA. torresjf@moffitt.usf.edu
authors.forename: Javier F
authors.initials: JF
authors.lastname: Torres-Roca
authors.forename: Steven
authors.initials: S
authors.lastname: Eschrich
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhao
authors.forename: Gregory
authors.initials: G
authors.lastname: Bloom
authors.forename: Jimmy
authors.initials: J
authors.lastname: Sung
authors.forename: Susan
authors.initials: S
authors.lastname: McCarthy
authors.forename: Alan B
authors.initials: AB
authors.lastname: Cantor
authors.forename: Anna
authors.initials: A
authors.lastname: Scuto
authors.forename: Changgong
authors.initials: C
authors.lastname: Li
authors.forename: Suming
authors.initials: S
authors.lastname: Zhang
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
authors.forename: Timothy
authors.initials: T
authors.lastname: Yeatman
mesh_terms: D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000532:radiotherapy*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D016133:Polymerase Chain Reaction; D011836:Radiation Tolerance / Q000235:genetics*; D015203:Reproducibility of Results; D056505:Retinoblastoma-Binding Protein 4; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D009687:Nuclear Proteins; C082637:RBBP4 protein, human; D056505:Retinoblastoma-Binding Protein 4