Microrna-based methods and compositions for the diagnosis, prognosis and treatment of tumor involving chromosomal rearrangements

Abstract

Provided are novel methods and compositions for the diagnosis, prognosis and treatment of tumor involving a chromosomal rearrangement, in particular a tumor or neoplasia of the thyroid gland. In addition, methods of identifying anti-tumor agents are described.

1 . A method of diagnosing whether a subject has, or is at risk for developing a tumor with a chromosomal rearrangement, the method comprising measuring the level of at least one microRNA (miR) in a test sample from the subject, wherein the presence or increased level of the miR in the test sample, relative to the level of a corresponding miR in a control sample, is indicative of the subject either having, or being at risk for developing said tumor, wherein the miR is or belongs to the C19MC or miR-371-3 cluster. 
     
     
         2 . The method of  claim 1 , wherein the chromosomal rearrangement is a translocation. 
     
     
         3 . The method of  claim 1 , wherein the chromosomal rearrangement is present on chromosome 19. 
     
     
         4 . The method of  claim 3 , wherein the chromosomal rearrangement involves chromosomal band 19q13. 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the level of at least one miR of the C19MC cluster and at least one miR of the miR-371-3 cluster is measured. 
     
     
         8 . The method of  claim 1 , wherein the miR of the C19MC cluster is hsa-mir-371; hsa-miR-371-3p; hsa-miR-371-5p; hsa-miR-372; hsa-miR-373; hsa-miR-373*; hsa-mir-512-1; hsa-miR-512-5p; hsa-miR-512-3p; hsa-mir-512-2; hsa-miR-512-5p; hsa-miR-512-3p; hsa-mir-515-1; hsa-miR-515-5p; hsa-miR-515-3p; hsa-mir-515-2; hsa-miR-515-5p; hsa-miR-515-3p; hsa-mir-516a-1; hsa-miR-516a-5p; hsa-miR-516a-3p; hsa-mir-516a-2; hsa-miR-516a-5p; hsa-miR-516a-3p; hsa-mir-516b-1; hsa-miR-516b; hsa-miR-516b*; hsa-mir-518b; hsa-miR-517a; hsa-miR-517*; hsa-miR-517b; has-miR-517*; hsa-mir-517c; hsa-miR-517*; hsa-mir-518a-1; hsa-miR-518a-5p; hsa-miR-518a-3p; hsa-mir-518a-2; hsa-miR-518a-5p; hsa-miR-518a-3p; hsa-miR-518b; hsa-miR-518c; hsa-miR-518c*; hsa-mir-518d; hsa-miR-518d-5p; hsa-miR-518d-3p; hsa-miR-518e; hsa-miR-518e*; hsa-mir-518f; hsa-miR-518f*; hsa-mir-519a-1; hsa-miR-519a; hsa-miR-519a*; hsa-mir-519a-2; hsa-mir-519b; hsa-miR-519b-5p; hsa-miR-519b-3p; hsa-mir-519c; hsa-miR-519c-5p; hsa-miR-519c-3p; hsa-miR-519d; hsa-mir519e; hsa-miR-519e; hsa-miR-519e*; hsa-mir-520a; hsa-miR-520a-5p; hsa-miR-520a-3p; hsa-miR-520b; hsa-mir-520c; hsa-miR-520c-5p; hsa-miR-520c-3p; hsa-mir-520d; hsa-miR-520d-5p; hsa-miR-520d-3p; hsa-mir-520e; hsa-miR-520f; hsa-miR-520g; hsa-miR-520h; hsa-mir-521-1; hsa-mir-521-2; hsa-miR-521; hsa-mir-522; hsa-miR-522*; hsa-mir-523; hsa-miR-523*; hsa-mir-524; hsa-miR-524-5p; hsa-miR-524-3p; hsa-mir-525; hsa-miR-525-5p; hsa-miR-525-3p; hsa-mir-526a-1; hsa-miR-526a; hsa-mir-526a-2; hsa-mir-526b; hsa-miR-526b*; or hsa-miR-527. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 1 , wherein the tumor is associated with one or more prognostic markers in a subject. 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the subject is a human. 
     
     
         14 . (canceled) 
     
     
         15 . A method for treating a subject suffering from a tumor with a chromosomal rearrangement, said method comprising administering to a subject a compound capable of inhibiting expression of at least one miR that is or belongs to the C19MC or miR-371-3 cluster. 
     
     
         16 . The method of  claim 15 , wherein the subject has been diagnosed in accordance with a method comprising measuring the level of at least one microRNA (miR) in a test sample from the subject, wherein the presence or increased level of the miR in the test sample, relative to the level of a corresponding miR in a control sample, is indicative of the subject either having, or being at risk for developing said tumor, wherein the miR is or belongs to the C19MC or miR-371-3 cluster. 
     
     
         17 . The method of  claim 16 , wherein the miR is miR-373 and the tumor is a tumor or neoplasia of the thyroid gland. 
     
     
         18 . A method of inhibiting proliferation of a cell of a tumor involving a chromosomal rearrangement comprising:
 (i) introducing into the cell one or more agents which inhibit expression or activity of one or more miRs which expression is induced or increased in the tumor cell having a chromosomal rearrangement, relative to a control cell; and   (ii) maintaining the cell under conditions in which the one or more agents inhibits expression or activity of the miR, thereby inhibiting proliferation of the tumor cell.   
     
     
         19 . A method of identifying an anti-tumor agent for a tumor, comprising providing a test agent to a cell and measuring the level of at least one miR associated with increased expression levels in tumor cells having a chromosomal rearrangement, wherein a decrease in the level of the miR in the cell, relative to a suitable control cell, is indicative of the test agent being an anti-tumor agent. 
     
     
         20 . The method of  claim 18 , wherein the tumor is a tumor or neoplasia of the thyroid gland and the cell is a thyroid adenoma cell. 
     
     
         21 . A kit for use in comprising one or more reagents for detecting one or more miRs wherein the miR is or belongs to the C19MC or miR-371-3 cluster. 
     
     
         22 . The kit according to  claim 21 , wherein the one or more reagent is selected from the group consisting of a primer specific for one or more miRs and a probe specific for one or more miRs wherein the one or more miRs is or belongs to the C19MC or miR-371-3 cluster. 
     
     
         23 . The method of  claim 17 , wherein the at least one miR comprises miR-512-5p, miR-517a, miR-519a, miR-520c, miR-371-3p, miR-372 and/or miR-373. 
     
     
         24 . The kit of  claim 21 , wherein the at least one miR comprises miR-512-5p, miR-517a, miR-519a, miR-520c, miR-371-3p, miR-372 and/or miR-373. 
     
     
         25 . The method of  claim 1 , wherein the test sample is a blood or tissue sample.