Methods for predicting prostate cancer and uses thereof

Abstract

The present invention relates to compositions and methods for diagnosing, prognosing, monitoring, and treating a patient with prostate cancer. In particular, the invention relates to the use of miRNA and snoRNA as expression signatures for identifying a clinically significant prostate cancer.

1 . A system for classifying a human test subject as having prostate cancer or no prostate cancer comprising:
 a processor for performing a PCa (Prostate Cancer) Test configured to:
 (a) interrogate sncRNA sequences for a set of informative sequences comprising a panel of hybridizing probes of SEQ ID NOs: 1-280 in a first high throughput microarray platform; 
 (b) determine a test score (PCa score) that examines the aggregate expression profile of all the interrogated sequences of SEQ ID NOs: 1-280 in a first Classification algorithm,
 wherein the first Classification algorithm is trained on a cohort of participants whose core-needle biopsy is positive (known to have prostate cancer) and a cohort of participant whose core-needle biopsy is negative (known to have no prostate cancer); 
 
 (c) compare the test score (PCa score) in (b) for the interrogated informative sequences to a score obtained in training data sets from patients known to have prostate cancer or patients with no prostate cancer; and 
 (d) classify with a specificity of at least 90-95% whether the human test subject has:
 prostate cancer when the test score (PCa score) from the human test subject is statistically greater or equal to the score in the training data set from a target population having prostate cancer; or 
 no prostate cancer when the test score (PCa score) from the human test subject is statistically less than or equal to the score in the training data set from a target population having no prostate cancer. 
 
   
     
     
         2 . The system of  claim 1 , wherein sncRNAs are extracted from a prostate derived biological sample and reversed transcribed to cDNAs. 
     
     
         3 . The system of  claim 2 , wherein the prostate derived biological sample comprises sncRNA extracted from urinary exosome isolated from cell free urine. 
     
     
         4 . The system of  claim 3 , wherein the sncRNA comprises miRNA, C/D box snoRNA, H/ACA box snoRNA, scaRNA, piRNA, and lncRNA. 
     
     
         5 . The system of  claim 3 , wherein the sncRNA comprises a miRNA and a snoRNA. 
     
     
         6 . The system of  claim 1 , wherein the hybridizing probes are specific for each of the cDNA derived from sncRNAs obtained from a prostate derived biological sample. 
     
     
         7 . The system of  claim 6 , wherein the hybridizing probes detect at least SEQ ID NOs: 2, 6, 14, 20, 31, 56, 64, 67, 79, 82, 91, 92, and 161. 
     
     
         8 . The system of  claim 1 , wherein the human test subject determined to have prostate cancer requires further testing to classify the human test subject as having indolent (low grade or GG1) or intermediate/high grade (GG2-GG5) prostate cancer; and the human subject determined to have no prostate cancer requires monitoring. 
     
     
         9 . The system of  claim 8 , wherein the human test subject classified to have no prostate cancer requires routine follow-up urine test every 12 months. 
     
     
         10 . A system for classifying a human test subject identified to have prostate cancer as having indolent (low grade, GG1), or intermediate/high grade (GG2-GG5) prostate cancer comprising:
 a processor for performing a CS (Clinically Significant) Test configured to:
 (a) interrogate sncRNA sequences for a set of informative sequences comprising a panel of hybridizing probes specific for each of the cDNA derived from sncRNAs obtained from a prostate derived biological sample, wherein the hybridizing probes detect of SEQ ID NOs: 281-560 in a second high throughput microarray platform; 
 (b) determine a test score (CS Score) that examine the aggregate expression profile of all the interrogated sequences of SEQ ID NOs: 281-560 in a second Classification algorithm,
 wherein the second Classification algorithm is trained on a cohort of participants known to have low grade (GG1) prostate cancer, and another cohort of participants known to have intermediate/high grade (GG2-GG5) prostate cancer; 
 
 (c) compare the test score (CS Score) in (b) for the interrogated informative sequences to a score obtained in training data sets from patients known to have indolent (low grade, GG1) or intermediate/high grade (GG2-GG5) prostate cancer; and 
 (d) determine with a specificity of at least 90-95% that the human test subject has:
 indolent prostate cancer (low grade, GG1) when the CS score from the human test subject is statistically less than or equal to the CS score in the training data set from a target population having indolent prostate cancer (low grade, GG1), or 
 intermediate/high grade (GG2-GG5) prostate cancer when the CS score from the human test subject is statistically greater than or equal to the CS score in the training data set from a target population having intermediate/high grade (GG2-GG5) prostate cancer, 
 wherein 
 the human test subject determined to have high grade (GG2-GG5) prostate cancer is further tested to determine if the human test subject has low/intermediate risk (GG1-GG2) or aggressive (high grade, GG3-GG5) prostate cancer. 
 
   
     
     
         11 . The system of  claim 10 , wherein the hybridizing probes detect at least SEQ ID NOs: 22, 281, 283, 284, 285, 286, 287, 313, 316, 321, 336, 337, 340, 363 and 371. 
     
     
         12 . The system of  claim 10 , wherein the human test subject determined to have intermediate/high grade (GG2-GG5) prostate cancer requires further testing to classify the human test subject as having low/intermediate grade (GG1-GG2), or high grade/aggressive (GG3-GG5) prostate cancer; and the human test subject determined to have indolent (low grade or GG1) prostate cancer requires monitoring for a routine follow-up urine test every 6 to 12 months. 
     
     
         13 . A system for classifying if a human test subject identified to have intermediate/high grade (GG2-GG5) prostate cancer as having low/intermediate grade (GG1-GG2) or high grade/aggressive (GG3-GG5) prostate cancer comprising:
 a processor for performing a high grade (HG) test configured to
 (a) interrogate sncRNAs sequences for a set of informative sequences comprising a panel of hybridizing probes specific for each of the cDNA derived from sncRNAs obtained from a prostate derived biological sample, wherein the hybridizing probes detect SEQ ID NOs: 561-840 on a third high throughput microarray platform; 
 (b) determine a test score (HG Score) that examines the aggregate expression profile of all the interrogated sequences of SEQ ID NOs: 561-840 in a third Classification algorithm,
 wherein the third Classification algorithm is trained on a cohort of participants known to have low/intermediate grade (GG1-GG2) prostate cancer, and another cohort of participants known to have high grade/aggressive (GG3-GG5) prostate cancer; 
 
 (c) compare the test score (HG Score) in (b) for the interrogated informative sequences to a score obtained in training data sets from patients known to have low/intermediate risk (GG1-GG2) or high grade/aggressive (GG3-GG5) prostate cancer; and 
 (d) determine with a sensitivity of at least 90-95% whether the human test subject has:
 low/intermediate risk (GG1-GG2) prostate cancer when the test score (HG Score) from the human test subject is statistically less than or equal to the HG score in the training date set from a target population low/intermediate grade (GG1-GG2) prostate cancer, or 
 high grade/aggressive (GG3-GG5) prostate cancer when the test score (HG Score) from the human test subject is statistically greater than or equal to the HG score in the training date set from a target population high grade/aggressive (GG3-GG5) prostate cancer. 
 
   
     
     
         14 . The system of  claim 13 , wherein the hybridizing probes detect at least SEQ ID NOs: 111, 178, 291, 318, 346, 347, 389, 503, 580, 620, 704, 708, 766, 791, and 797. 
     
     
         15 . The system of  claim 13 , wherein the human test subject determined to have high grade/aggressive (GG3-GG5) prostate cancer requires treatment; and the human test subject determined to have low/intermediate grade (GG1-GG2) prostate cancer requires the urine test as part of an active surveillance every 3 or 6 months. 
     
     
         16 . The system of  claim 15 , wherein the subject classified as having aggressive (intermediate or high grade, GG2-GG5) prostate cancer is treated with one or more of radical prostatectomy, brachytherapy of the prostate, radiotherapy of the prostate, neoadjuvant hormone therapy and adjuvant hormone therapy. 
     
     
         17 . A system for determining if a human test subject has cancer or no cancer, and classifying the human test subject with cancer as having (i) indolent (low grade, GG1), (ii) intermediate or high grade (GG2-GG5), (iii) low/intermediate risk (GG1-GG2) or (iv) aggressive (high grade, GG3-GG5) prostate cancer comprising:
 a first processor configured to:
 (a) interrogate sncRNA sequences for a first set of informative sequences comprising a panel of hybridizing probes comprising SEQ ID NOs: 1-280 in a first high throughput microarray platform; 
 (b) determine a test score (PCa score) that examines the aggregate expression profile of all the interrogated sequences of SEQ ID NOs: 1-280 and interaction between the sequences in a first Classification algorithm,
 wherein the first Classification algorithm is trained on a cohort of target population whose core-needle biopsy is positive (known to have prostate cancer) and a cohort of target population whose core-needle biopsy is negative (known to have no prostate cancer); 
 
 (c) compare the test score (PCa score) in (i)(b) for the interrogated informative sequences to a score obtained in training data sets from a target population known to have prostate cancer or no prostate cancer; and 
 (d) determine with a specificity of at least 90-95% whether the human test subject has:
 prostate cancer when the test score (PCa score) from the test subject is statistically greater than or equal to the score in the training data set from a target population having prostate cancer, or 
 no prostate cancer when the test score (PCa score) from the test subject is statistically less than or equal to the score in the training data set from a target population having no prostate cancer; 
 wherein 
 the human test subject determined to have prostate cancer is re-tested to classify if the human test subject has indolent (low grade, GG1) or intermediate or high grade (GG2-GG5) prostate cancer; 
 
   (ii) a second processor configured to:
 (a) interrogate sncRNA sequences for a second set of informative sequences comprising a panel of hybridizing probes comprising SEQ ID NOs: 281-560 in a second high throughput microarray platform; 
 (b) determine a second test score (Clinically Significant (CS) score) that examines the aggregate expression profile of all the interrogated sequences of SEQ ID NOs: 281-560 and interaction between the sequences in a second Classification algorithm,
 wherein 
 the second Classification algorithm is trained on a cohort of target population known to have indolent (low grade, GG1), and another cohort of target population known to have intermediate/high grade (GG2-GG5) prostate cancer; 
 
 (c) compare the test score (CS score) in (ii)(b) for the interrogated informative sequences to a score obtained in training data sets from target population known to have indolent (low grade, GG1) or high grade (GG2-GG5) prostate cancer; and 
 (d) determine with a specificity of at least 90-95% whether the human test subject has:
 indolent (low grade, GG1) prostate cancer when the CS score from the human test subject is statistically less than or equal to the CS score in the training data set from a target population having indolent prostate cancer (low grade, GG1), or 
 high grade (GG2-GG5) prostate cancer when the CS score from the human test subject is statistically less than or equal to the CS score in the training data set from a target population having intermediate/high grade (GG2-GG5) prostate cancer, 
 wherein 
 the human test subject determined to have high grade (GG2-GG5) prostate cancer is retested to further classify if the human test subject has low/intermediate risk (GG1-GG2) or aggressive (high grade, GG3-GG5) prostate cancer; 
 
   (iii) a third processor configured to
 (a) interrogate sncRNAs sequences for a third set of informative sequences comprising a panel of hybridizing probes comprising SEQ ID NOs: 561-840 in a third high throughput microarray platform; 
 (b) determine a third test score (HG score) that examine the aggregate expression profile of all the interrogated sequences of SEQ ID NOs: 561-840 and interaction between the sequences in a third Classification algorithm; 
 (c) compare the HG score in (iii)(b) for the interrogated informative sequences to a score obtained in training data sets from target population known to have low/intermediate risk (GG1-GG2) or aggressive (high grade, GG3-GG5) prostate cancer; and 
 (d) determine with a specificity of at least 90-95% whether the test subject has:
 low/intermediate risk (GG1-GG2) when the test score (HG Score) from the human test subject is statistically less than or equal to the HG score in the training date set from a target population low/intermediate grade (GG1-GG2) prostate cancer, or 
 aggressive (high grade, GG3-GG5) prostate cancer when the test score (HG Score) from the human test subject is statistically greater than or equal to the HG score in the training date set from a target population high grade/aggressive (GG3-GG5) prostate cancer. 
 
   
     
     
         18 . The system of  claim 17 , wherein sncRNAs are extracted from a prostate derived biological sample, and wherein the extracted sncRNA are reverse transcribed to cDNAs. 
     
     
         19 . The system of  claim 17 , wherein the hybridizing probes are specific for each of the cDNA derived from sncRNAs obtained from a prostate derived biological sample. 
     
     
         20 . The system of  claim 17 , where the human test subject classified as having aggressive (high grade, GG3-GG5) prostate cancer requires one or more treatments including radical prostatectomy, brachytherapy of the prostate, radiotherapy of the prostate, neoadjuvant hormone therapy and adjuvant hormone therapy; the test subject determined to have low/intermediate grade (GG1-GG2) prostate cancer requires routine follow-up urine test or active surveillance every 6-12 months; and test subject determined to have intermediate/high grade (GG2-GG5) requires routine follow-up urine test or active surveillance every 3-6 months.