Gene Signature for the Prediction of Radiation Therapy Response

Abstract

Described are mathematical models and method, e.g., computer-implemented methods, for predicting tumor sensitivity to radiation therapy, which can be used, e.g., for selecting a treatment for a subject who has a tumor.

1 . A method of predicting the sensitivity of a cell to a selected dose of radiation therapy, the method comprising:
 assigning a radiation sensitivity index to the cell based on expression levels of two or more signature genes in the cell, wherein the two or more signature genes are selected from the group consisting of Androgen receptor (AR); Jun oncogene (c-Jun); Signal transducer and activator of transcription 1 (STAT1); Protein kinase C, beta (PRKCB or PKC); V-rel reticuloendotheliosis viral oncogene homolog A (avian) (RELA or p65); c-Abl oncogene 1, receptor tyrosine kinase (ABL1 or c-Abl); SMT3 suppressor of mif two 3 homolog 1 ( S. cerevisiae ) (SUMO1); CDK1 (p34); Histone deacetylase 1 (HDAC1); and Interferon regulatory factor 1 (IRF1);   wherein the radiation sensitivity index indicates whether the cell is sensitive to radiation therapy.   
   
   
       2 . The method of  claim 1 , wherein assigning a radiation sensitivity index comprises applying a linear regression model to the gene expression levels. 
   
   
       3 . The method of  claim 2 , wherein the model is a rank-based linear regression model. 
   
   
       4 . The method of  claim 1 , wherein the cell is a tumor cell. 
   
   
       5 . The method of  claim 1 , wherein the two or more signature genes are weighted. 
   
   
       6 . The method of  claim 5 , wherein the linear regression model is represented by the following algorithm:
   RSI= k   1 *AR+k 2   *c - jun+k   3 *STAT1 +k   4 *PKC+ k   5 *Rel A+k   6   *cAbl+k   7   *SUMO 1 +k   8   *CDK 1 +k   9   *HDAC+k   10 *IRF1.  I   
   
   
       7 . The method of  claim 1 , wherein the method is computer-implemented. 
   
   
       8 . The method of  claim 1 , wherein assigning a radiation sensitivity index comprises:
 determining a level of expression of the two or more genes in the cell.   
   
   
       9 . The method of  claim 1 , wherein the signature genes comprise AR, c-jun, STAT1, cAbl, SUMO1, and IRF1. 
   
   
       10 . The method of  claim 1 , wherein the signature genes comprise c-jun, STAT1, RelA, cAbl, SUMO1, and IRF1. 
   
   
       11 . The method of  claim 1 , wherein the signature genes comprise c-jun, STAT1, PKC, RelA, cAbl, HDAC, and IRF1. 
   
   
       12 . The method of  claim 1 , wherein the signature genes comprise AR, c-jun, STAT1, PKC, RelA, cAbl, HDAC, and IRF1. 
   
   
       13 . The method of  claim 1 , wherein the signature genes comprise AR, c-jun, STAT1, PKC, RelA, cAbl, SUMO1, CDK1, HDAC, and IRF1. 
   
   
       14 . A computer-implemented method of identifying genes associated with radiation sensitivity, the method comprising:
 assigning a radiation sensitivity value to one or more populations of cells, wherein the radiation sensitivity value represents the sensitivity of the cells to a selected dose of radiation;   determining a level of gene expression in the one or more populations of cells for each of a plurality of genes; and   identifying a subset comprising two or more genes, the expression of which is correlated with the radiation sensitivity value.   
   
   
       15 . The method of  claim 14 , wherein identifying a subset of the genes comprises applying a model representing gene expression and radiosensitivity. 
   
   
       16 . The method of  claim 15 , wherein the model is a multivariate linear regression model. 
   
   
       17 . The method of  claim 15 , wherein the model includes at least one coefficient representing one, two, or all three of: tissue of origin, ras status, or p53 status. 
   
   
       18 . The method of  claim 15 , further comprising associating a classifier representing biological importance with each gene in the subset of genes, expression of which is correlated with the radiation sensitivity value, and selecting a second subset comprising two or more genes wherein the classifier representing biological importance is above a preselected threshold, thereby selecting a subset of biologically important genes. 
   
   
       19 . The method of  claim 18 , wherein the model further comprises a variable representing an effect of administration of a treatment on expression of each gene in the subset of biologically important genes. 
   
   
       20 . The method of  claim 19 , further comprising selecting a third subset comprising one or more genes based on the effect of administration of the treatment, thereby identifying a subset of therapeutic target genes. 
   
   
       21 . The method of  claim 20 , wherein the effect of the treatment is an increase in radiosensitivity. 
   
   
       22 . The method of  claim 20 , wherein the effect of the treatment is a decrease in radiosensitivity. 
   
   
       23 . The method of  claim 19 , further comprising selecting a treatment that has an effect on radiosensitivity in the model. 
   
   
       24 . A method of predicting the effect of radiation therapy on a tumor, the method comprising:
 assigning a radiation sensitivity index to the tumor based on expression levels of two or more signature genes in a cell from the tumor, wherein the two or more signature genes are selected from the group consisting of Androgen receptor (AR); Jun oncogene (c-Jun); Signal transducer and activator of transcription 1 (STAT1); Protein kinase C, beta (PRKCB or PKC); V-rel reticuloendotheliosis viral oncogene homolog A (avian) (RELA or p65); c-Abl oncogene 1, receptor tyrosine kinase (ABL1 or c-Abl); SMT3 suppressor of mif two 3 homolog 1 ( S. cerevisiae ) (SUMO1); CDK1 (p34); Histone deacetylase 1 (HDAC1); and Interferon regulatory factor 1 (IRF1);   wherein the radiation sensitivity index indicates whether the radiation therapy is likely to be effective.   
   
   
       25 . A method of assessing a tumor in a subject for a radiation therapy regimen, the method comprising:
 assigning a radiation sensitivity index to the tumor based on expression levels of two or more signature genes in a cell from the tumor, wherein the two or more signature genes are selected from the group consisting of Androgen receptor (AR); Jun oncogene (c-Jun); Signal transducer and activator of transcription 1 (STAT1); Protein kinase C, beta (PRKCB or PKC); V-rel reticuloendotheliosis viral oncogene homolog A (avian) (RELA or p65); c-Abl oncogene 1, receptor tyrosine kinase (ABL1 or c-Abl); SMT3 suppressor of mif two 3 homolog 1 ( S. cerevisiae ) (SUMO1); CDK1 (p34); Histone deacetylase 1 (HDAC1); and Interferon regulatory factor 1 (IRF1);   wherein the radiation sensitivity index indicates whether the tumor in the subject should be treated with radiation therapy.   
   
   
       26 . A method of selecting a treatment regimen for a subject having a tumor, the method comprising:
 assigning a radiation sensitivity index to the tumor based on expression levels of two or more signature genes in a cell from the tumor, wherein the two or more signature genes are selected from the group consisting of Androgen receptor (AR); Jun oncogene (c-Jun); Signal transducer and activator of transcription 1 (STAT1); Protein kinase C, beta (PRKCB or PKC); V-rel reticuloendotheliosis viral oncogene homolog A (avian) (RELA or p65); c-Abl oncogene 1, receptor tyrosine kinase (ABL1 or c-Abl); SMT3 suppressor of mif two 3 homolog 1 ( S. cerevisiae ) (SUMO1); CDK1 (p34); Histone deacetylase 1 (HDAC1); and Interferon regulatory factor 1 (IRF1); and   selecting a treatment regimen for the subject based on the radiation sensitivity index.   
   
   
       27 . The method of  claim 26 , wherein a radiation sensitivity index below a threshold indicates that radiation therapy is likely to be effecting in treating the tumor, and the method includes selecting a treatment regimen including radiation therapy. 
   
   
       28 . The method of  claim 26 , wherein a radiation sensitivity index above a threshold indicates that radiation therapy is not likely to be effecting in treating the tumor, and the method includes selecting a treatment regimen excluding radiation therapy, or a treatment regime including a high dose of radiation therapy. 
   
   
       29 . A method of selecting a dose of radiation to be administered to a subject having a tumor, the method comprising:
 assigning to the tumor a radiation sensitivity index for a preselected dose of radiation based on expression levels of two or more signature genes in a cell from the tumor, wherein the two or more signature genes are selected from the group consisting of Androgen receptor (AR); Jun oncogene (c-Jun); Signal transducer and activator of transcription 1 (STAT1); Protein kinase C, beta (PRKCB or PKC); V-rel reticuloendotheliosis viral oncogene homolog A (avian) (RELA or p65); c-Abl oncogene 1, receptor tyrosine kinase (ABL1 or c-Abl); SMT3 suppressor of mif two 3 homolog 1 ( S. cerevisiae ) (SUMO1); CDK1 (p34); Histone deacetylase 1 (HDAC1); and Interferon regulatory factor 1 (IRF1); and   selecting a dose of radiation for the subject based on the radiation sensitivity index at the preselected dose of radiation.   
   
   
       30 . The method of  claim 29 , comprising selecting a dose of radiation that is the same as or less than the preselected dose of radiation, if the radiation sensitivity index is below a threshold. 
   
   
       31 . The method of  claim 26 , comprising selecting a dose of radiation that is the greater than the preselected dose of radiation, if the radiation sensitivity index is above a threshold. 
   
   
       32 . A database comprising a plurality of records wherein each record includes data on the expression of at least two signature genes in a cell, wherein the two or more signature genes are selected from the group consisting of Androgen receptor (AR); c-Jun; STAT1; PKC; RelA (p65); c-Abl; SUMO-1; CDK1 (p34); HDAC1; and IRF1, and a value representing sensitivity of the cell to a selected dose of radiation. 
   
   
       33 . The database of  claim 29 , further comprising data regarding the administration of a treatment to the cell. 
   
   
       34 . The database of  claim 29 , wherein the treatment is the administration of chemotherapy. 
   
   
       35 . The database of  claim 29 , wherein the database is in computer readable form. 
   
   
       36 . A microarray comprising a substrate and a plurality of individually addressable hybridisable array elements arranged thereon, wherein the individually addressable hybridisable array elements are selective for at least two signature genes selected from the group consisting of Androgen Receptor (AR); c-Jun; STAT1; PKC; RelA (p65); c-Abl; SUMO-1; CDK1 (p34); HDAC1; and IRF1; and optionally at least one hybridisable array element selective for an internal normalization control gene. 
   
   
       37 . The microarray of  claim 33 , wherein the plurality of hybridisable array elements consists of at least one element selective for each of the Androgen Receptor (AR); c-Jun; STAT1; PKC; RelA (p65); c-Abl; SUMO-1; CDK1 (p34); HDAC1; and IRF1. 
   
   
       38 . A microfluidic device comprising a substrate and a plurality of reaction chambers, wherein the reaction chambers comprise reagents for selective quantification of at least two signature genes selected from the group consisting of Androgen Receptor (AR); c-Jun; STAT1; PKC; RelA (p65); c-Abl; SUMO-1; CDK1 (p34); HDAC1; and IRF1; and optionally at least one reaction chamber comprising reagents for selective quantification of an internal normalization control gene. 
   
   
       39 . The microfluidic device of  claim 35 , wherein the plurality of reaction chambers comprise reagents for selective quantification of each of the Androgen Receptor (AR); c-Jun; STAT1; PKC; RelA (p65); c-Abl; SUMO-1; CDK1 (p34); HDAC1; IRF1; and at least one reaction chamber comprising reagents for selective quantification of an internal normalization control gene. 
   
   
       40 . A medium bearing instructions to cause a computer to assign a radiation sensitivity index to a cell based on expression levels of two or more signature genes in the cell, wherein the two or more signature genes are selected from the group consisting of Androgen receptor (AR); Jun oncogene (c-Jun); Signal transducer and activator of transcription 1 (STAT1); Protein kinase C, beta (PRKCB or PKC); V-rel reticuloendotheliosis viral oncogene homolog A (avian) (RELA or p65); c-Abl oncogene 1, receptor tyrosine kinase (ABL1 or c-Abl); SMT3 suppressor of mif two 3 homolog 1 ( S. cerevisiae ) (SUMO1); CDK1 (p34); Histone deacetylase 1 (HDAC1); and Interferon regulatory factor 1 (IRF1). 
   
   
       41 . The medium of  claim 33 , in which assigning a radiation sensitivity index comprises applying a linear regression model to the gene expression levels. 
   
   
       42 . The medium of  claim 33 , wherein the model is a rank-based linear regression model. 
   
   
       43 . The medium of  claim 33 , wherein the signature genes consist of the Androgen Receptor (AR); c-Jun; STAT1; PKC; RelA (p65); c-Abl; SUMO-1; CDK1 (p34); HDAC 1; and IRF1. 
   
   
       44 . The medium of  claim 33 , wherein the two or more signature genes are weighted. 
   
   
       45 . A medium bearing instructions to cause a computer to:
 assign a radiation sensitivity value to one or more populations of cells, wherein the radiation sensitivity value represents the sensitivity of the cells to a selected dose of radiation;   assign a level of gene expression in the one or more populations of cells for each of a plurality of genes; and   identify a subset comprising two or more genes, the expression of which is correlated with the radiation sensitivity value.   
   
   
       46 . The medium of  claim 42 , wherein identifying a subset of the genes comprises applying a model representing gene expression and radiosensitivity. 
   
   
       47 . The medium of  claim 43 , wherein the model is a multivariate linear regression model. 
   
   
       48 . The medium of  claim 43 , wherein the model includes at least one coefficient representing one, two, or all three of: tissue of origin, ras status, or p53 status. 
   
   
       49 . The medium of  claim 43 , wherein the medium further comprises instructions to cause a computer to associate a classifier representing biological importance with each gene in the subset of genes, expression of which is correlated with the radiation sensitivity value, and to select a second subset comprising two or more genes wherein the classifier representing biological importance is above a preselected threshold, thereby selecting a subset of biologically important genes. 
   
   
       50 . The medium of  claim 46 , wherein the model further comprises a variable representing an effect of administration of a treatment on expression of each gene in the subset of biologically important genes. 
   
   
       51 . The medium of  claim 47 , further comprising selecting a third subset comprising two or more genes based on the effect of administration of the treatment, thereby identifying a subset of therapeutic target genes. 
   
   
       52 . A kit comprising reagents for the specific quantification of gene expression levels of two or more signature genes in a cell, wherein the two or more signature genes are selected from the group consisting of Androgen receptor (AR); Jun oncogene (c-Jun); Signal transducer and activator of transcription 1 (STAT1); Protein kinase C, beta (PRKCB or PKC); V-rel reticuloendotheliosis viral oncogene homolog A (avian) (RELA or p65); c-Abl oncogene 1, receptor tyrosine kinase (ABL1 or c-Abl); SMT3 suppressor of mif two 3 homolog 1 ( S. cerevisiae ) (SUMO1); CDK1 (p34); Histone deacetylase 1 (HDAC1); and Interferon regulatory factor 1 (IRF1).