Prognostic and Predictive Gene Signature for Non-Small Cell Lung Cancer and Adjuvant Chemotherapy

Abstract

The application provides methods of prognosing and classifying lung cancer patients into poor survival groups or good survival groups and for determining the benefit of adjuvant chemotherapy by way of a multigene signature. The application also includes kits and computer products for use in the methods of the application.

1 - 44 . (canceled) 
     
     
         45 . A method for prognosing or classifying a subject with non-small cell lung cancer (NSCLC) comprising:
 obtaining at least one tumor sample from a subject;   isolating RNA from the sample;   labeling the RNA and/or converting the RNA to cDNA;   determining by microarray or quantitative PCR relative expression levels of at least 15 biomarkers in the tumor sample from the subject, wherein the at least 15 biomarkers comprise FAM64A, MB, EDN3, ZNF236, FOSL2, MYT1L, MLANA, L1 CAM, TRIM14, STMN2, UMPS, ATP1B1, HEXIM1, IKBKAP, and MDM2;   calculating a combined score from the relative expression levels, including the relative expression levels of FAM64A, MB, EDN3, ZNF236, FOSL2, MYT1L, MLANA, L1CAM, TRIM14, STMN2, UMPS, ATP1B1, HEXIM1, IKBKAP, and MDM2, and   classifying the subject into a high or low risk group for a poor or good survival outcome and/or a poor or good response to adjuvant chemotherapy based on the combined score.   
     
     
         46 . The method of  claim 45 , further comprising selecting adjuvant chemotherapy if the subject is in the high risk group. 
     
     
         47 . The method of  claim 45 , further comprising selecting resection alone for the low risk group. 
     
     
         48 . The method of  claim 45 , wherein the combined score is calculated from the relative expression levels of 16, 17, or 18 biomarkers. 
     
     
         49 . The method of  claim 48 , wherein the one, two or three additional biomarkers are selected from Table 3. 
     
     
         50 . The method of  claim 49 , wherein the additional one, two, or three biomarkers are selected from RGS4, UGT2B4, and MCF2. 
     
     
         51 . The method of  claim 45 , wherein the combined score is calculated according to Formula I;
   Combined score=0.557× PC 1+0.328× PC 2+0.43× PC 3+0.335× PC 4  (e I),
   wherein PC1 is the sum of the relative expression level for each biomarker multiplied by a first principal component for each biomarker, PC2 is the sum of the relative expression level for each biomarker multiplied by a second principal component for each biomarker, PC3 is the sum of the relative expression level for each biomarker multiplied by a third principal component for each biomarker, and PC4 is the sum of the relative expression level of each biomarker multiplied by a fourth principal component for each biomarker.   
     
     
         52 . The method of  claim 45 , wherein the subject has stage I or stage II NSCLC. 
     
     
         53 . A method for prognosing or classifying a subject with stage I or stage II non-small cell lung cancer (NSCLC) comprising:
 obtaining at least one tumor sample from a subject with stage I or stage II NSCLC;   isolating RNA from the sample;   labeling the RNA and/or converting the RNA to cDNA;   determining by microarray or quantitative PCR relative expression levels of at least 15 biomarkers in the tumor sample from the subject, wherein the at least 15 biomarkers comprise FAM64A, MB, EDN3, ZNF236, FOSL2, MYT1L, MLANA, L1CAM, TRIM14, STMN2, UMPS, ATP1B1, HEXIM1, IKBKAP, and MDM2;   calculating a combined score from the relative expression levels, including the relative expression levels of FAM64A, MB, EDN3, ZNF236, FOSL2, MYT1L, MLANA, L1 CAM, TRIM14, STMN2, UMPS, ATP1B1, HEXIM1, IKBKAP, and MDM2;   classifying the subject into a high or low risk group for a poor or good survival outcome and/or a poor or good response to adjuvant chemotherapy based on the combined score, and   selecting adjuvant chemotherapy if the subject is in the high risk group, or selecting resection alone if the subject is in the low risk group.   
     
     
         54 . The method of  claim 53 , wherein the combined score is calculated from the relative expression levels of 16, 17, or 18 biomarkers. 
     
     
         55 . The method of  claim 54  wherein the one, two or three additional biomarkers are selected from Table 3. 
     
     
         56 . The method of  claim 55  wherein the additional one, two, or three biomarkers are selected from RGS4, UGT2B4, and MCF2. 
     
     
         57 . The method of  claim 53  wherein the combined score is calculated according to Formula I:
   Combined score=0.557× PC 1+0.328× PC 2+0.43× PC 3+0.335× PC 4  (Formula I),
 
 wherein PC1 is the sum of the relative expression level for each biomarker multiplied by a first principal component for each biomarker, PC2 is the sum of the relative expression level for each biomarker multiplied by a second principal component for each biomarker, PC3 is the sum of the relative expression level for each biomarker multiplied by a third principal component for each biomarker, and PC4 is the sum of the relative expression level of each biomarker multiplied by a fourth principal component for each biomarker.