Survival predictor for diffuse large b cell lymphoma

Abstract

The invention provides methods and materials related to a gene expression-based survival predictor for diffuse large B cell lymphoma (DLBCL) patients.

1 - 32 . (canceled) 
     
     
         33 . A method of predicting the survival outcome of a subject suffering from diffuse large B cell lymphoma (DLBCL), which method comprises:
 a) isolating gene expression product from one or more DLBCL biopsy samples from a subject;   b) obtaining a gene expression profile from the gene expression product, wherein the expression profile comprises an expression level for each gene in a germinal center B cell (GCB) gene expression signature and a stromal-1 gene expression signature;   c) determining a GCB signature value and a stromal-1 signature value from the gene expression profile; and   d) calculating a survival predictor score using an equation that includes subtracting [(x)*(the GCB signature value)] and subtracting [(y)*(the stromal-1 signature value)], wherein (x) and (y) are scale factors and wherein a lower survival predictor score indicates a more favorable survival outcome and a higher survival predictor score indicates a less favorable survival outcome for the subject.   
     
     
         34 . The method of  claim 33 , wherein the GCB signature value corresponds to the average of the expression levels of the genes in the GCB gene expression signature and the stromal-1 signature value corresponds to the average of the expression levels of the genes in the stromal-1 gene expression signature. 
     
     
         35 . The method of  claim 33 , wherein the method comprises:
 b) obtaining a gene expression profile from the gene expression product, wherein the expression profile comprises an expression level for each gene in a GCB expression signature, a stromal-1 gene expression signature, and a stromal-2 gene expression signature;   c) determining a GCB signature value, a stromal-1 signature value, and a stromal-2 signature value from the gene expression profile; and   d) calculating a survival predictor score using an equation that includes subtracting [(x)*(the GCB signature value)] and subtracting [(y)*(the stromal-1 signature value)], and adding [(z)*(the stromal-2 signature value)], wherein (x), (y), and (z) are scale factors and wherein a lower survival predictor score indicates a more favorable survival outcome and a higher survival predictor score indicates a less favorable survival outcome for the subject.   
     
     
         36 . The method of  claim 35 , wherein the the GCB signature value corresponds to the average of the expression levels of the genes in the GCB gene expression signature, the stromal-1 signature value corresponds to the average of the expression levels of the genes in the stromal-1 gene expression signature, and the stromal-2 signature value corresponds to the average of the expression levels of the genes in the stromal-2 gene expression signature. 
     
     
         37 . The method of  claim 35 , wherein the method comprises:
 d) calculating a survival predictor score using the equation: survival predictor score=8.11−[0.419*(the GCB signature value)]−[1.015*(the stromal-1 signature value)]+[0.675*(the stromal-2 signature value)], wherein a lower survival predictor score indicates a more favorable survival outcome and a higher survival predictor score indicates a less favorable outcome for the subject.   
     
     
         38 . A method of evaluating a therapeutic regimen for a DLBCL patient based on survival outcome, wherein the method comprises:
 a) isolating gene expression product from one or more DLBCL biopsy samples from a subject;   b) obtaining a gene expression profile from the gene expression product, wherein the expression profile comprises an expression level for each gene in a germinal center B cell (GCB) gene expression signature and a stromal-1 gene expression signature;   c) determining a GCB signature value and a stromal-1 signature value from the gene expression profile; and   d) calculating a survival predictor score using an equation that includes subtracting [(x)*(the GCB signature value)] and subtracting [(y)*(the stromal-1 signature value)], wherein (x) and (y) are scale factors and wherein (i) a lower survival predictor score indicates a more favorable survival outcome and a therapeutic regimen that includes chemotherapy and Rituximab (R-CHOP) and (ii) a higher survival predictor score indicates a less favorable survival outcome and a therapeutic regimen other than R-CHOP.   
     
     
         39 . The method of  claim 38 , wherein the DCLBCL patient suffered relapse from R-CHOP treatment. 
     
     
         40 . The method of  claim 38 , wherein the GCB signature value corresponds to the average of the expression levels of the genes in the GCB gene expression signature and the stromal-1 signature value corresponds to the average of the expression levels of the genes in the stromal-1 gene expression signature. 
     
     
         41 . The method of  claim 38 , wherein the method comprises:
 b) obtaining a gene expression profile from the gene expression product, wherein the expression profile comprises an expression level for each gene in a GCB expression signature, a stromal-1 gene expression signature, and a stromal-2 gene expression signature;   c) determining a GCB signature value, a stromal-1 signature value, and a stromal-2 gene signature value from the gene expression profile; and   d) calculating a survival predictor score using an equation that includes subtracting [(x)*(the GCB signature value)] and subtracting [(y)*(the stromal-1 signature value)], and adding [(z)*(the stromal-2 signature value)], wherein (x), (y), and (z) are scale factors and wherein (i) a lower survival predictor score indicates a more favorable survival outcome and a therapeutic regimen that includes chemotherapy and Rituximab (R-CHOP) and (ii) a higher survival predictor score indicates a less favorable survival outcome and a therapeutic regimen other than R-CHOP.   
     
     
         42 . The method of  claim 41 , wherein the the GCB signature value corresponds to the average of the expression levels of the genes in the GCB gene expression signature, the stromal-1 signature value corresponds to the average of the expression levels of the genes in the stromal-1 gene expression signature, and the stromal-2 signature value corresponds to the average of the expression levels of the genes in the stromal-2 gene expression signature. 
     
     
         43 . The method of  claim 41 , wherein the method comprises:
 d) calculating a survival predictor score using the equation: survival predictor score=8.11−[0.419*(the GCB signature value)]−[1.015*(the stromal-1 signature value)]+[0.675*(the stromal-2 signature value)] and wherein (i) a lower survival predictor score indicates a more favorable survival outcome and a therapeutic regimen that includes chemotherapy and Rituximab (R-CHOP) and (ii) a higher survival predictor score indicates a less favorable survival outcome and a therapeutic regimen other than R-CHOP.   
     
     
         44 . A method of treating a subject with DLBCL, the method comprising evaluating a therapeutic regimen for a DLBCL patient according to the method of  claim 38  and providing a therapeutic regimen based on the indication of the survival predictor score, wherein a lower survival predictor indicates treatment with a therapeutic regimen that includes chemotherapy and Rituximab (R-CHOP) and a higher survival predictor score indicates a less favorable survival outcome and a therapeutic regimen other than R-CHOP. 
     
     
         45 . The method of  claim 44 , wherein evaluating a therapeutic regimen includes the method of  claim 41 . 
     
     
         46 . A method of predicting the survival outcome of a subject suffering from diffuse large B cell lymphoma (DLBCL), which method comprises:
 a) obtaining one or more DLBCL biopsy samples from a subject;   b) isolating gene expression product from the one or more DLBCL biopsy samples;   c) obtaining a gene expression profile from the gene expression product, wherein the expression profile comprises an expression level for each gene in a germinal center B-cell gene (GCB) expression signature, a stromal-1 gene expression signature, and a stromal-2 gene expression signature;   c) determining a GCB signature value, a stromal-1 signature value, and a stromal-2 signature value from the gene expression profile; and   d) calculating a survival predictor score using the equation: survival predictor score=A−[(x)*(the GCB signature value)]−[(y)*(the stromal-1 signature value)]+[(z)*(the stromal-2 signature value)], wherein A is an offset term and (x), (y), and (z) are scale factors; and   e) calculating the probability of a survival outcome for the subject beyond an amount of time t following treatment for DLBCL, wherein the subject's probability of the survival outcome P(SO) is calculated using the equation: P(SO)=SO 0 (t) (exp((s)*survival predictor score)) , wherein SO 0 (t) is the probability of the survival outcome, which corresponds to the largest time value smaller than t in a survival outcome curve, and wherein (s) is a scale factor.   
     
     
         47 . The method of  claim 46 , wherein the survival outcome is overall survival and the method comprises:
 d) calculating a survival predictor score using the equation: survival predictor score=[0.419*(the GCB signature value)]−[1.015*(the stromal-1 signature value)]+[0.675*(the stromal-2 signature value)]; and   e) calculating the probability of overall survival after time t for the subject, wherein the subject's probability of overall survival P(OS) is calculated using the equation: P(OS)=OS 0 (t) (exp(survival predictor score)) , wherein OS 0 (t) is the probability of overall survival, which corresponds to the largest time value smaller than t in an overall survival curve, and wherein scale factor (s)=1.   
     
     
         48 . The method of  claim 46 , wherein the survival outcome is progression free survival and the method comprises:
 d) calculating a survival predictor score using the equation: survival predictor score=8.11−[0.419*(the GCB signature value)]−[1.015*(the stromal-1 signature value)]+[0.675*(the stromal-2 signature value)]; and   e) calculating the probability of progression free survival after time t for the subject, wherein the subject's probability of progression free survival P(PFS) is calculated using the equation P(PFS)=F 0 (t) (exp(0.976*survival predictor score)) , wherein F 0 (t) is the probability of progression free survival, which corresponds to the largest time smaller than t in a survival curve, and wherein wherein scale factor (s)=0.976.   
     
     
         49 . The method of  claim 46 , wherein the the GCB signature value corresponds to the average of the expression levels of the genes in the GCB gene expression signature, the stromal-1 signature value corresponds to the average of the expression levels of the genes in the stromal-1 gene expression signature, and the stromal-2 signature value corresponds to the average of the expression levels of the genes in the stromal-2 gene expression signature. 
     
     
         50 . The method of  claim 46 , wherein the treatment for DLCBL includes the administration Rituximab. 
     
     
         51 . The method of  claim 46 , wherein the method further includes providing the subject with the calculated probability of the survival outcome after time t. 
     
     
         52 . A method of evaluating a subject for antiangiogenic therapy of DLBCL, which method comprises:
 a) isolating gene expression product from one or more DLBCL biopsy samples from a subject;   b) obtaining a gene expression profile from the gene expression product, wherein the profile includes an expression level for each gene in a stromal-2 signature;   c) determining the subject's stromal-2 signature value from the gene expression profile; and   d) determining whether the subject's stromal-2 signature value is higher or lower than a standard stromal-2 value, wherein antiangiogenic therapy is indicated by a stromal-2 signature value that is higher than the standard stromal-2 value and antiangiogenic therapy is not indicated by a stromal-2 signature value that is not higher than the standard stromal-2 value.