Tert promoter mutations in cancer

Abstract

The present invention relates to the field of cancer. More specifically, the present invention provides methods and compositions related to certain promoter mutations in cancer. In one embodiment, a method for treating a subject having thyroid cancer comprises the steps of (a) obtaining a biological sample from the subject (b) performing an assay on the sample obtained from the subject to identify a mutation at 1 295 228 C>T (C228T) and 1 295 250 C>T (C250T), corresponding to −124 C>T and −146 C>T from the translation start site in the promoter of the telomerase reverse transcriptase (TERT) gene; (c) identifying the subject as having or likely to develop aggressive thyroid cancer if the C228T and/or C250T mutation is identified; and (d) treating the subject with one or more treatment modalities appropriate for a subject having or likely to develop aggressive thyroid cancer.

1 - 11 . (canceled) 
     
     
         12 . A method for treating a subject having bladder cancer comprising the steps of:
 (a) contacting DNA extracted from a biological sample obtained from the subject with at least one primer that specifically hybridizes to the telomerase reverse transcriptase (TERT) gene;   (b) amplifying by polymerase chain reaction (PCR) a region of the TERT gene that comprises −124 and −146 from the translation start site in the promoter of the TERT gene;   (c) sequencing the amplification product to detect the presence of a mutation at −124 (C228T) and/or −146 (C250T) from the translation start site in the promoter of the TERT gene; and   (d) treating the subject having the C228T mutation and/or C250T mutation with one or more treatment modalities appropriate for a subject having bladder cancer, wherein the treatment modalities comprise transurethral resection, radical cystectomy, partial cystectomy, urinary diversion, radiation therapy, chemotherapy, bacillus Calmette Guerin (BCG) immunotherapy and combinations thereof.   
     
     
         13 . The method of  claim 12 , wherein the treatment modalities further comprise administering to the subject a TERT inhibitor, wherein the TERT inhibitor comprises BIBR1532, TMPyP4, MST312, MnTMPyp pentachloride, BPPA, .beta.-Rubromycin, Trichostatin A, Costunolide, Doxorubicin, Suramin Sodium or (−)-Epigallocatechin Gallate. 
     
     
         14 . The method of  claim 12 , wherein the at least one primer of step (a) comprises SEQ ID NO:2 and/or SEQ ID NO:3. 
     
     
         15 . A method for identifying a subject having bladder cancer as likely to develop aggressive bladder cancer comprising the steps of:
 (a) contacting DNA extracted from a biological sample obtained from the subject with at least one primer that specifically hybridizes to the TERT gene, where in the at least one primer comprises SEQ ID NO:2 and/or SEQ ID NO:3;   (b) amplifying by PCR a region of the TERT gene that comprises −124 and −146 from the translation start site in the promoter of the TERT gene; and   (c) sequencing the amplification product to detect the presence of a C228T mutation and/or a C250T mutation, wherein the detection of the mutation indicates the subject is likely to develop aggressive bladder cancer.   
     
     
         16 . The method of  claim 15 , further comprising the step of administering a treatment modality appropriate for a subject having or likely to develop aggressive bladder cancer, wherein the treatment modality comprises transurethral resection, radical cystectomy, partial cystectomy, urinary diversion, radiation therapy, chemotherapy,  bacillus  Calmette Guerin (BCG) immunotherapy and combinations thereof. 
     
     
         17 . The method of  claim 16 , wherein the treatment modality further comprises administering to the subject a TERT inhibitor, wherein the TERT inhibitor comprises BIBR1532, TMPyP4, MST312, MnTMPyp pentachloride, BPPA, .beta.-Rubromycin, Trichostatin A, Costunolide, Doxorubicin, Suramin Sodium or (−)-Epigailocatechin Gallate. 
     
     
         18 . A method for treating a subject having glioblastoma comprising the steps of:
 (a) contacting DNA extracted from a biological sample obtained from the subject with at least one primer that specifically hybridizes to the telomerase reverse transcriptase (TERT) gene;   (b) amplifying by polymerase chain reaction (PCR) a region of the TERT gene that comprises −124 and −146 from the translation start site in the promoter of the TERT gene;   (c) sequencing the amplification product to detect the presence of a mutation at −124 (C228T) and/or −146 (C250T) from the translation start site in the promoter of the TERT gene; and   (d) treating the subject having the C228T mutation and/or C250T mutation with one or more treatment modalities appropriate for a subject having glioblastoma, wherein the treatment modalities comprise surgery, radiation therapy, chemotherapy, biologic therapy and combinations thereof.   
     
     
         19 . The method of  claim 18 , wherein the treatment modalities further comprise administering to the subject a TERT inhibitor, wherein the TERT inhibitor comprises BIBR1532, TMPyP4, MST312, MnTMPyp pentachloride, BPPA, .beta.-Rubromycin, Trichostatin A, Costunolide, Doxorubicin, Suramin Sodium or (−)-Epigallocatechin Gallate. 
     
     
         20 . The method of  claim 18 , wherein the at least one primer of step (a) comprises SEQ ID NO:2 and/or SEQ ID NO:3. 
     
     
         21 . A method for identifying a subject as having glioblastoma or likely to develop glioblastoma comprising the steps of:
 (a) contacting DNA extracted from a biological sample obtained from the subject with at least one primer that specifically hybridizes to the TERT gene, where in the at least one primer comprises SEQ ID NO:2 and/or SEQ ID NO:3;   (b) amplifying by PCR a region of the TERT gene that comprises −124 and −146 from the translation start site in the promoter of the TERT gene; and   (c) sequencing the amplification product to detect the presence of a C228T mutation and/or a C250T mutation, wherein the detection of the mutation indicates the subject as having or likely to develop glioblastoma.   
     
     
         22 . The method of  claim 21 , further comprising the step of administering a treatment modality appropriate for a subject having or likely to develop glioblastoma, wherein the treatment modality comprises surgery, radiation therapy, chemotherapy, biologic therapy and combinations thereof. 
     
     
         23 . The method of  claim 22 , wherein radiation therapy comprises 3-dimensional radiation therapy, intensity-modulated radiation therapy, stereotactic radiation therapy or proton beam radiation therapy. 
     
     
         24 . The method of  claim 22 , wherein biologic therapy comprises tyrosine kinase inhibitor therapy, vascular endothelial growth factor (VEGF) therapy, dendritic call vaccine therapy or gene therapy. 
     
     
         25 . The method of  claim 22 , wherein the treatment modality further comprises administering to the subject a TERT inhibitor, wherein the TERT inhibitor comprises BIBR1532, TMPyP4, MST312, MnTMPyp pentachloride, BPPA, .beta.-Rubromycin, Trichostatin A, Costunolide, Doxorubicin, Suramin Sodium or (−)-Epigailocatechin Gallate.