Methods And Marker Combinations For Screening For Predisposition To Lung Cancer

Abstract

The present invention relates to rapid, sensitive methods for determining whether a subject is at risk of developing lung cancer or has lung cancer based on certain combinations or biomarkers or biomarkers and biometric parameters.

1 . A method of aiding in a diagnosis of a subject suspected of lung cancer, the method comprising the steps of:
 a. quantifying in a test sample obtained from a subject, the amount of two or more biomarkers in a panel;   b. comparing the amount of each biomarker quantified in the panel to a predetermined cutoff for said biomarker and assigning a score for each biomarker based on said comparison;   c. combining the assigned score for each biomarker quantified in step b to obtain a total score for said subject;   d. comparing the total score determined in step c with a predetermined total score; and   e. determining whether said subject has a risk of lung cancer based on the comparison of the total score in step d,   wherein the biomarkers quantified are at least anti-p53, anti-NY-ESO-1, anti-MAPKAPK3, and anti-Cyclin E2.   
     
     
         2 . The method of  claim 1 , wherein the panel further comprises at least one antibody selected from the group consisting of: anti TMP21, anti-HDJ1, anti-NPC1L1C-domain, anti-TMOD1, anti-CAMK1, anti-RGS1, anti-PACSIN1, and anti-RCV1. 
     
     
         3 . The method of  claim 1 , wherein the panel further comprises at least one antigen selected from the group consisting of: cytokeratin 8, cytokeratin 19, cytokeratin 18, CEA, CA125, CA19-9, CA15-3, SCC, proGRP, serum amyloid A, alpha-1-anti-trypsin, apolipoprotein CIII, and thymosin β4. 
     
     
         4 . The method of  claim 1 , wherein the panel further comprises at least one region of interest selected from the group consisting of: Acn6399, Acn9459, Pub11597, Pub4789, TFA2759, TFA9133, Pub3743, Pub8606, Pub4487, Pub4861, Pub6798, Pub6453, Pub2951, Pub2433, Pub17338, TFA6453, and HIC3959. 
     
     
         5 . The method of  claim 1 , wherein the DFI of the biomarkers relative to lung cancer is less than about 0.4. 
     
     
         6 . The method of  claim 1 , wherein step b comprises comparing the amount of each biomarker in the panel to a number of predetermined cutoffs for said biomarker and assigning a score for each biomarker based on said comparison, step c comprises combining the assigned score for each biomarker quantified in step b to obtain a total score for said subject, step d comprises comparing the total score determined in step c with a predetermined total score, and step e comprises determining whether said subject has lung cancer based on the comparison of the total score in step d. 
     
     
         7 . A method of aiding in a diagnosis of a subject suspected of lung cancer, the method comprising the steps of:
 a. obtaining a value for at least one biometric parameter of a subject;   b. comparing the value of the at least one biometric parameter against a predetermined cutoff for each said biometric parameter and assigning a score for each biometric parameter based on said comparison;   c. quantifying in a test sample obtained from a subject, the amount of two or more biomarkers in a panel;   d. comparing the amount of each biomarker quantified in the panel to a predetermined cutoff for said biomarker and assigning a score for each biomarker based on said comparison;   e. combining the assigned score for each biometric parameter determined in step b with the assigned score for each biomarker quantified in step d to obtain a total score for said subject;   f. comparing the total score determined in step e with a predetermined total score; and   g. determining whether said subject has a risk of lung cancer based on the comparison of the total score in step f,   wherein the biomarkers quantified are at least anti-p53, anti-NY-ESO-1, anti-MAPKAPK3, and anti-Cyclin E2.   
     
     
         8 . The method of  claim 7 , wherein the panel further comprises at least one antibody selected from the group consisting of: anti TMP21, anti-HDJ1, anti-NPC1L1C-domain, anti-TMOD1, anti-CAMK1, anti-RGS1, anti-PACSIN1, and anti-RCV1. 
     
     
         9 . The method of  claim 7 , wherein the panel further comprises at least one antigen selected from the group consisting of: cytokeratin 8, cytokeratin 19, cytokeratin 18, CEA, CA125, CA19-9, CA15-3, SCC, proGRP, serum amyloid A, alpha-1-anti-trypsin, apolipoprotein CIII, and thymosin β4. 
     
     
         10 . The method of  claim 7 , wherein the panel further comprises at least one region of interest selected from the group consisting of: Acn6399, Acn9459, Pub11597, Pub4789, TFA2759, TFA9133, Pub3743, Pub8606, Pub4487, Pub4861, Pub6798, Pub6453, Pub2951, Pub2433, Pub17338, TFA6453 and HIC3959. 
     
     
         11 . The method of  claim 7 , wherein the biometric parameter is selected from the group consisting of: the subject's smoking history, age, carcinogen exposure and gender. 
     
     
         12 . The method of  claim 11 , wherein the biometric parameter is pack-years of smoking. 
     
     
         13 . The method of  claim 7 , wherein step b comprises comparing the value of each biometric parameter against a number of predetermined cutoffs for said biometric parameter and assigning one of a number of possible scores for each said biometric parameter based on said comparison, step d comprises comparing the amount of each biomarker in the panel to a number of predetermined cutoffs for said biomarker and assigning a score for each biomarker based on said comparison, step e comprises combining the assigned score for each biomarker quantified in step d with the assigned score for the biometric parameter in step b to obtain a total score for said subject, step f comprises comparing the total score determined in step e with a predetermined total score and step g comprises determining whether said subject has lung cancer based on the comparison of the total score in step f. 
     
     
         14 . The method of  claim 1 , wherein the anti-Cyclin E2 is an antibody against SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5. 
     
     
         15 . The method of  claim 7 , wherein the anti-Cyclin E2 is an antibody against SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5. 
     
     
         16 . A kit comprising:
 a. reagents containing antigens for quantifying anti-p53, anti-NY-ESO-1, anti-MAPKAPK3, and anti-Cyclin E2 in a test sample;   b. reagents containing at least one antibody for quantifying one or more antigens in a test sample, wherein said antigens are: cytokeratin 8, cytokeratin 19, cytokeratin 18, CEA, CA125, CA15-3, SCC, CA19-9, proGRP, serum amyloid A, alpha-1-anti-trypsin, apolipoprotein CIII or thymosin β4;   c. reagents containing one or more antigens for quantifying at least one antibody in a test sample, wherein said antibodies are: anti-TMP21, anti-NPC1LIC-domain, anti-TMOD1, anti-HDJ1, anti-CAMK1, anti-RGS1, anti-PACSIN1, or anti-RCV1; and optionally,   d. algorithms for combining and comparing the amount of each antigen and antibody quantified in the test sample against a predetermined cutoff and assigning a score for each antigen and antibody quantified based on said comparison, combining the assigned score for each antigen and antibody quantified to obtain a total score, comparing the total score with a predetermined total score and using said comparison as an aid in determining whether a subject has lung cancer.   
     
     
         17 . The kit of  claim 16 , further comprising reagents for quantifying one or more regions of interest selected from the group consisting of: ACN9459, Pub11597, Pub4789, TFA2759, TFA9133, Pub3743, Pub8606, Pub4487, Pub4861, Pub6798, Tfa6453 and Hic3959. 
     
     
         18 . The kit of  claim 17 , wherein said kit contains reagents for quantifying each of cytokeratin 19, CEA, CA125 and ProGRP in a test sample. 
     
     
         19 . The kit of  claim 17 , wherein said kit contains reagents for quantifying each of cytokeratin 19, CEA, CA125, ProGRP, anti-p53, anti-NY-ESO-1, anti-MAPKAPK3 and anti-Cyclin E2 in a test sample. 
     
     
         20 .- 33 . (canceled)