Prognostic method for individuals with prostate cancer

Abstract

The present invention relates generally to the detection and identification of various forms of genetic markers, and various forms of proteins, which have the potential utility as diagnostic markers. By determining the level of a plurality of biomarkers and genetic markers in a patient sample, and combining the obtained values according to a predefined formula, it is possible to forecast if it is likely that the prostate cancer patient will require active therapy like radiation therapy or surgery. A method based on a redundantly designed combination of data is disclosed for estimating if prostate cancer is aggressive or indolent. Said method combines SNP data to form a composite value, wherein at least 5% of the SNPs can be disregarded.

1 . A method based on a redundantly designed combination of data for estimating if an individual diagnosed with prostate cancer will require active therapy, comprising the steps of:
 1. Providing at least one biological sample from said individual;   2. In said biological sample, analyzing a category of SNPs related to PCa (SNPpc), by measuring a presence or absence of each of a plurality of SNPpc;   3. Combining data regarding said category of SNPpc to form a SNPpc composite value, wherein the method allows disregarding a subset of at least 5% of the SNPpc of the SNPpc category when forming the SNPpc composite value;   4. Correlating said SNPpc composite value to the likelihood of the individual requiring active therapy, by comparing the SNPpc composite value to a pre-determined cut-off value established with control samples, wherein it is known if the individuals, from whom the control samples originate, required active therapy or did not require active therapy.   
     
     
         2 . The method of  claim 1 , wherein the SNPpc include at least two of rs11672691, rs11704416, rs3863641, rs12130132, rs4245739, rs3771570, rs7611694, rs1894292, rs6869841, rs2018334, rs16896742, rs2273669, rs1933488, rs11135910, rs3850699, rs11568818, rs1270884, rs8008270, rs4643253, rs684232, rs11650494, rs7241993, rs6062509, rs1041449, rs2405942, rs12621278, rs9364554, rs10486567, rs6465657, rs2928679, rs6983561, rs16901979, rs16902094, rs12418451, rs4430796, rs11649743, rs2735839, rs9623117, and rs138213197. 
     
     
         3 . The method of  claim 1  or  2 , further comprising analyzing, in said biological sample, a category of PCa biomarkers, by measuring a presence or concentration of each of a plurality of PCa biomarkers of said category of PCa biomarkers; combining data regarding said category of PCa biomarkers to form a biomarker composite value; combining the biomarker composite value and the SNPpc composite value to form an overall composite value; and correlating said overall composite value to the likelihood of said individual requiring active therapy by comparing the overall composite value to a pre-determined value established with control samples, wherein it is known if the individuals, from which the control samples originate, required active therapy or did not require active therapy. 
     
     
         4 . The method of  claim 3 , comprising measuring the presence or concentration of at least partially redundant PCa biomarkers, and wherein at least one, such as two, of the PCa biomarkers is selected from the group consisting of (i) PSA, (ii) total PSA (tPSA), (iii) intact PSA (iPSA), (iv) free PSA (fPSA), and (v) hK2. 
     
     
         5 . The method of  claim 4 , wherein the method allows disregarding a subset of at least one of said PCa biomarkers (i)-(v) of the PCa biomarker category when forming said biomarker composite value, such as a subset of one, two, three, or four of said PCa biomarkers (i)-(v). 
     
     
         6 . The method of any one of the preceding claims, wherein the method allows disregarding at least 10%, such as 15%, such as 20%, such as 30% of the SNPpc of the SNPpc category when forming the SNPpc composite value. 
     
     
         7 . The method of any one of the preceding claims, wherein said data regarding said category of SNPpc are combined according to a predetermined equation to form said SNPpc composite value. 
     
     
         8 . The method of any one of  claims 3 - 7 , wherein said data regarding said category of PCa biomarkers are combined according to a predetermined equation to form said biomarker composite value. 
     
     
         9 . The method of any one of  claims 3 - 8 , wherein said biomarker composite value and said SNPpc composite value are combined according to a predetermined equation to form said overall composite value. 
     
     
         10 . The method of any one of the preceding claims, further comprising recommending the individual for active therapy if the SNPpc composite value or the overall composite value is greater than the cut-off value. 
     
     
         11 . The method of any one of  claims 3 - 10 , further comprising analyzing, in said biological sample, a category of SNPs related to a PCa biomarker concentration (SNPbm), by measuring a presence or absence of at least one SNPbm; combining data regarding said SNPbm to form a SNPbm composite value; and including the SNPbm composite value in the overall composite value. 
     
     
         12 . The method of  claim 11 , wherein the SNPbm includes at least one of rs3213764, rs1354774, rs1227732, rs2736098, rs401681, rs10788160, rs11067228, rs1363120, rs888663, and rs1054564. 
     
     
         13 . The method of any one of  claims 3 - 12 , further comprising analyzing, in said biological sample, a category of SNP related to the Body Mass Index of said individual (SNPbmi), by measuring a presence or absence of at least one SNPbmi; combining data regarding said category of SNPbmi to form a SNPbmi composite value; and including said SNPbmi composite value in the overall composite value. 
     
     
         14 . The method of  claim 13 , wherein the SNPbmi includes at least one of rs3817334, rs10767664, rs2241423, rs7359397, rs7190603, rs571312, rs29941, rs2287019, rs2815752, rs713586, rs2867125, rs9816226, rs10938397, and rs1558902. 
     
     
         15 . The method of any one of the preceding claims, further comprising collecting the family history regarding PCa, treatment history, and physical data from said individual; and wherein said family history, treatment history and/or physical data are included in the overall composite value. 
     
     
         16 . The method of any one of  claims 3 - 15 , further comprising analyzing an additional category of PCa biomarkers, by measuring the presence or concentration of one or each of a plurality of PCa biomarkers of said additional biomarker category; combining data regarding said additional PCa biomarker category to form an additional biomarker composite value for said additional PCa biomarker category; and including said additional biomarker composite value in the overall composite value; wherein the combination of data to form the additional biomarker composite value is redundantly designed where the additional category of PCa biomarkers comprises more than one PCa biomarker. 
     
     
         17 . The method of  claim 16 , wherein the additional category of PCa biomarkers comprises the biomarker MIC-1 and optionally other MIC-1 related biomarkers, or the biomarker MSMB and optionally other MSMB related biomarkers. 
     
     
         18 . The method of any one of the preceding claims, wherein said biological sample is a blood sample. 
     
     
         19 . The method of any one of  claims 11 - 18 , wherein the overall composite value is calculated using a method in which the non-additive effect of a SNPbm and the corresponding PCa biomarker concentration is utilized. 
     
     
         20 . The method of any one of the preceding claims, wherein the measurement of the presence or absence of said SNPs is conducted by use of MALDI mass spectrometry. 
     
     
         21 . The method of any one of the preceding claims, wherein the measurement of the presence or concentration of said PCa biomarkers is conducted by use of microarray technology. 
     
     
         22 . The method of any one of the preceding claims, wherein measuring the presence or absence of a SNP comprises measuring the number of alleles of said SNP. 
     
     
         23 . An assay device for performing step 2 of  claim 1 , comprising a solid phase having a category of ligands immobilized thereon, which binds specifically to a SNPpc, and including a plurality of different ligands binding specifically to each of a plurality of SNPpc, such as at least one of rs11672691, rs11704416, rs3863641, rs12130132, rs4245739, rs3771570, rs7611694, rs1894292, rs6869841, rs2018334, rs16896742, rs2273669, rs1933488, rs11135910, rs3850699, rs11568818, rs1270884, rs8008270, rs4643253, rs684232, rs11650494, rs7241993, rs6062509, rs1041449, or rs2405942, rs12621278, rs9364554, rs10486567, rs6465657, rs2928679, rs6983561, rs16901979, rs16902094, rs12418451, rs4430796, rs11649743, rs2735839, rs9623117 and rs138213197. 
     
     
         24 . The assay device of  claim 23  for performing the method of  claim 3 , wherein the solid phase further has a second category of ligand immobilized, which binds specifically to a PCa biomarker, and includes a plurality of different ligands binding specifically to each of a plurality of PCa biomarkers, such as at least one of PSA, iPSA, tPSA, fPSA, and hK2, and optionally MSMB and/or MIC-1. 
     
     
         25 . The assay device of  claim 23  or  24  for performing the method of  claim 11 , wherein the solid phase further has a third category of ligand immobilized, which binds specifically to a SNPbm, such as at least one of rs1227732, rs3213764, rs1354774, rs2736098, rs401681, rs10788160, rs11067228, rs1363120, rs888663, and rs1054564. 
     
     
         26 . The assay device of any one of  claims 23 - 25  for performing the method of  claim 13 , wherein the solid phase further has a fourth category of ligand immobilized, which binds specifically to a SNPbmi, such as at least one of rs3817334, rs10767664, rs2241423, rs7359397, rs7190603, rs571312, rs29941, rs2287019, rs2815752, rs713586, rs2867125, rs9816226, rs10938397, and rs1558902. 
     
     
         27 . A test kit for performing step 2 of  claim 1 , comprising an assay device according to  claim 23  and a category of detection molecules which is capable of detecting a SNPpc, such as at least one of rs11672691, rs11704416, rs3863641, rs12130132, rs4245739, rs3771570, rs7611694, rs11894292, rs6869841, rs2018334, rs16896742, rs2273669, rs1933488, rs11135910, rs3850699, rs11568818, rs1270884, rs8008270, rs4643253, rs684232, rs11650494, rs7241993, rs6062509, rs1041449, or rs2405942, rs12621278, rs9364554, rs10486567, rs6465657, rs2928679, rs6983561, rs16901979, rs16902094, rs12418451, rs4430796, rs11649743, rs2735839, rs9623117 and rs138213197. 
     
     
         28 . The test kit of  claim 27 , comprising an assay device according to  claim 24  and a second category of detection molecule, which is capable of detecting a PCa biomarker, such as at least one of PSA, iPSA, tPSA, fPSA, and hK2, and optionally MSMB and/or MIC-1. 
     
     
         29 . The test kit of  claim 27  or  28 , comprising an assay device of  claim 25  and a third category of detection molecule, which is capable of detecting a SNPbm, such as at least one of rs1227732, rs3213764, rs1354774, rs2736098, rs401681, rs10788160, rs11067228, rs1363120, rs888663, and rs1054564. 
     
     
         30 . The test kit of any one of  claims 27 - 29 , comprising an assay device of  claim 26  and a fourth category of detection molecule, which is capable of detecting a SNPbmi, such as at least one of rs3817334, rs10767664, rs2241423, rs7359397, rs7190603, rs571312, rs29941, rs2287019, rs2815752, rs713586, rs2867125, rs9816226, rs10938397, and rs1558902. 
     
     
         31 . An assay device comprising a solid phase having immobilized thereon a category of ligands, which binds specifically to a SNPpc, and including a plurality of different ligands binding specifically to each of a plurality of different SNPpc selected from at least one of rs11672691, rs11704416, rs3863641, rs12130132, rs4245739, rs3771570, rs7611694, rs1894292, rs6869841, rs2018334, rs16896742, rs2273669, rs1933488, rs11135910, rs3850699, rs11568818, rs1270884, rs8008270, rs4643253, rs684232, rs11650494, rs7241993, rs6062509, rs1041449, or rs2405942, rs12621278, rs9364554, rs10486567, rs6465657, rs2928679, rs6983561, rs16901979, rs16902094, rs12418451, rs4430796, rs11649743, rs2735839, rs9623117 and rs138213197. 
     
     
         32 . The assay device of  claim 31 , wherein the solid phase further has a second category of ligand immobilized, which binds specifically to a PCa biomarker, and including a plurality of different ligands binding specifically to each of a plurality of different PCa biomarkers selected from at least one of PSA, iPSA, tPSA, fPSA, and hK2, and optionally MSMB and/or MIC-1. 
     
     
         33 . The assay device of  claim 31  or  32 , wherein the solid phase further has a third category of ligand immobilized, which binds specifically to a SNPbm, and including one or a plurality of different ligands binding specifically to one or each of a plurality of SNPbm selected from at least one of rs1227732, rs3213764, rs1354774, rs2736098, rs401681, rs10788160, rs11067228, rs1363120, rs888663, and rs1054564. 
     
     
         34 . The assay device of any one of  claims 31 - 33 , wherein the solid phase further has a fourth category of ligand immobilized, which binds specifically to a SNPbmi, and including one or a plurality of different ligands binding specifically to one or each of a plurality of different SNPbmi selected from at least one of rs3817334, rs10767664, rs2241423, rs7359397, rs7190603, rs571312, rs29941, rs2287019, rs2815752, rs713586, rs2867125, rs9816226, rs10938397, and rs1558902. 
     
     
         35 . A computer program product directly loadable into the internal memory of a digital computer, characterized in that said product comprises software code means for performing at least steps 3 and 4 of  claim 1 , such as steps 1-4 of  claim 1 . 
     
     
         36 . The computer program product of  claim 35 , further comprising software code means for performing the method of  claim 3 . 
     
     
         37 . The computer program product of  claim 35  or  36 , further comprising software code means for performing the method of  claim 11 . 
     
     
         38 . The computer program product of any one of  claims 35 - 37 , further comprising software code means for performing the method of  claim 13 . 
     
     
         39 . An apparatus comprising an assay device according to  claim 31  and a computer program product according to  claim 35 , or an assay device according to  claim 32  and a computer program product according to  claim 36 , or an assay device according to  claim 33  and a computer program product according to  claim 37 , or an assay device according to  claim 34  and a computer program product according to  claim 38 .