Risk scores based on human phosphodiesterase 4D variant 7 expression
Methods are described for stratifying patient risk for patients with prostate cancer and for providing a treatment recommendation to a patient based on a phosphodiesterase 4D variant 7 (PDE4D7) risk score. A diagnostic kit and a computer program product for the analysis and determination of the PDE4D7 risk score are also described.
1. A method of risk stratification for a subject with prostate cancer, the method comprising:
determining a gene expression profile for a biological sample obtained from the subject with prostate cancer, and wherein the gene expression profile includes an expression level for phosphodiesterase 4D variant 7 (PDE4D7); and
determining, by processor circuitry, a prognostic risk score for the subject based on the determined gene expression profile, wherein the prognostic risk score is determined with a scoring function that is derived from gene expression profiles for biological samples taken from a plurality of individuals that have been monitored for prostate cancer; and
wherein the gene expression profile determined for the biological sample obtained from the subject with prostate cancer is a normalized gene expression profile obtained by normalizing the expression level of at least the PDE4D7 variant to the expression of at least two reference genes; and
wherein the at least two reference genes include both Tubulin-Alpha-1b (TUBA1B) and Homo sapiens pumilio RNA-Binding Family Member (PUM1) but does not include Homo sapiens hypoxanthine phosphoribosyltransferase 1 (HPRT1) or Homo sapiens TATA box binding protein (TBP).
2. The method of claim 1 , wherein the determining of the gene expression profile determined for the biological sample obtained from the subject with prostate cancer comprises performing RT-qPCR on RNA extracted from the biological sample.
3. The method of claim 2 , wherein the determining of the gene expression profile includes determining a Cq value for PDE4D7 and each of the at least two reference genes and wherein the determining a prognostic risk score includes normalizing the PDE4D7 value using the value of each of at least two reference genes and computing the risk score as a linear function of the normalized score.
4. The method of claim 2 , wherein the PCR is performed with at least one primer and/or probe for measuring a reference gene selected from the group consisting of TUBA1B and PUM1.
5. The method of claim 1 , wherein the prognostic risk score is a value in a predefined range.
6. The method of claim 1 , further comprising categorizing the subject into one of a predefined set of risk groups, based on the prognostic risk score.
7. The method of claim 6 , wherein there are at least two risk groups.
8. The method of claim 6 , further comprising at least one of:
proposing, by the processor circuitry, a therapy for the subject based on the assigned risk group for the subject, at least two of the risk groups being associated with different therapies;
computing, by the processor circuitry, a disease progression risk prediction for the subject before or after prostate surgery; and
computing, by the processor circuitry, a therapy response prediction for the subject before or after prostate surgery.
9. The method of claim 8 , wherein the proposed therapy is selected from the group consisting of:
at least a partial prostatectomy;
an active therapy selected from radiation treatment, hormone therapy, chemotherapy, and a combination thereof;
observation without performing the at least a partial prostatectomy or the active therapy selected from radiation treatment, hormone therapy, chemotherapy, and the combination thereof.
10. The method of claim 8 , wherein the proposed therapy is further based on a second risk determination.
11. The method of claim 10 , wherein the proposed therapy based on the assigned risk group is different from a proposed therapy based only on the second risk determination.
12. A method of providing a therapy recommendation for a subject with prostate cancer, the method comprising:
determining a gene expression profile for a biological sample obtained from the subject with prostate cancer, and wherein the gene expression profile includes an expression level for phosphodiesterase 4D variant 7 (PDE4D7);
normalizing, by processor circuitry, the gene expression profile using an expression level for at least two reference genes including Tubulin-Alpha-1b (TUBA1B) and Homo sapiens pumilio RNA-Binding Family Member (PUM1);
determining, by the processor circuitry, a prognostic risk score for the subject based on the normalized gene expression profile determined for the subject;
categorizing, by the processor circuitry, the subject into a PDE4D7 risk group based on the prognostic risk score determined for the subject;
providing, by the processor circuitry, a therapy recommendation for the subject based on the PDE4D7 risk group categorization for the subject, and wherein the at least two reference genes include both TUBA1B and PUM1 but does not include HPRT1 or TBP.
13. The method of claim 1 , wherein none of PDE4D variants serves as a reference gene.