Aberrant mitochondrial dna, associated fusion transcripts and hybridization probes therefor

Abstract

The present invention provides novel mitochondrial fusion transcripts and the parent mutated mtDNA molecules that are useful for predicting, diagnosing and/or monitoring cancer. Hybridization probes complementary thereto for use in the methods of the invention are also provided.

1 . An isolated mitochondrial fusion transcript associated with cancer. 
     
     
         2 . The mitochondrial fusion transcript of  claim 1 , wherein the transcript comprises an insertion, translocation, deletion, duplication, recombination, rearrangement or combination thereof. 
     
     
         3 . The mitochondrial fusion transcript of  claim 2 , wherein the transcript comprises a deletion. 
     
     
         4 . The mitochondrial fusion transcript of  claim 3 , wherein the transcript comprises a sequence as set forth in any one of SEQ ID NOs:18 to 33 or 50. 
     
     
         5 . The mitochondrial fusion transcript of  claim 3 , wherein the transcript comprises a sequence as set forth in any one of SEQ ID NOs: 18-21, 23, 25-33 or 50. 
     
     
         6 . The mitochondrial fusion transcript of  claim 3 , wherein the transcript comprises the expressed RNA transcript of a deletion sequence set out in Table 1. 
     
     
         7 . A mitochondrial fusion protein corresponding to the fusion transcript of  claim 4  and having a sequence as set forth in any one of SEQ ID NOs: 34 to 49 and 52. 
     
     
         8 . An isolated mitochondrial DNA (mtDNA) encoding the fusion transcript of  claim 1 . 
     
     
         9 . The isolated mtDNA of  claim 8  having a sequence as set forth in any one of SEQ ID NOs: 2-17 or 51. 
     
     
         10 . A hybridization probe having a nucleic acid sequence complementary to at least a portion of the mitochondrial fusion transcript according to  claim 4 . 
     
     
         11 . A method of detecting a cancer in a mammal, the method comprising assaying a tissue sample from the mammal for the presence of at least one mitochondrial fusion transcript associated with cancer by hybridizing the sample with at least one hybridization probe having a nucleic acid sequence complementary to at least a portion of the mitochondrial fusion transcript according to  claim 4 . 
     
     
         12 . A method of detecting a cancer in a mammal, the method comprising assaying a tissue sample from the mammal for the presence of at least one aberrant mtDNA associated with cancer by hybridizing the sample with at least one hybridization probe having a nucleic acid sequence complementary to at least a portion of the mtDNA according to  claim 7 . 
     
     
         13 . The method of  claim 11 , wherein the cancer is prostate cancer, testicular cancer, ovarian cancer, breast cancer, colorectal cancer, lung cancer, melanoma skin cancer or combinations thereof. 
     
     
         14 . The method of  claim 13 , wherein the assay comprises:
 a) conducting a hybridization reaction using at least one of said probes to allow said at least one probe to hybridize to a complementary mitochondrial fusion transcript or mtDNA;   b) quantifying the amount of the at least one mitochondrial fusion transcript or mtDNA in said sample by quantifying the amount of said transcript or mtDNA hybridized to said at least one probe; and,   c) comparing the amount of the mitochondrial fusion transcript or mtDNA in the sample to at least one known reference value.   
     
     
         15 . The method of  claim 14 , wherein the assay is carried out using diagnostic imaging technology. 
     
     
         16 . The method of  claim 15 , wherein the diagnostic imaging technology comprises high throughput microarray analysis. 
     
     
         17 . The method of  claim 14 , wherein the assay is carried out using branched DNA technology. 
     
     
         18 . The method of  claim 14 , wherein the assay is carried out using PCR. 
     
     
         19 . A kit for conducting an assay for detecting the presence of a cancer in a mammal, said kit comprising at least one hybridization probe complementary to at least a portion of the fusion transcript of  claim 4 . 
     
     
         20 . A screening tool comprised of a microarray having 10's, 100's, or 1000's of mitochondrial fusion transcripts according to  claim 4  for identification of those associated with cancer. 
     
     
         21 . A screening tool comprised of a microarray having 10's, 100's, or 1000's of mitochondrial DNAs according to  claim 9  for identification of those associated with cancer. 
     
     
         22 . A screening tool comprised of a multiplexed branched DNA assay having 10's, 100's, or 1000's of mitochondrial fusion transcripts according to  claim 4  for identification of those associated with cancer. 
     
     
         23 . A screening tool comprised of a multiplexed branched DNA assay having 10's, 100's, or 1000's of mitochondrial DNAs according to  claim 9  for identification of those associated with cancer. 
     
     
         24 . A hybridization probe having a nucleic acid sequence complementary to at least a portion of the mitochondrial fusion transcript according to  claim 5 . 
     
     
         25 . A hybridization probe having a nucleic acid sequence complementary to at least a portion of a mitochondrial fusion transcript according to  claim 3 , wherein the transcript comprises the expressed RNA transcript of a deletion sequence set out in Table  1 . 
     
     
         26 . A hybridization probe having a nucleic acid sequence complementary to at least a portion of the mtDNA of  claim 9 . 
     
     
         27 . A method of detecting a cancer in a mammal, the method comprising assaying a tissue sample from the mammal for the presence of at least one mitochondrial fusion transcript associated with cancer by hybridizing the sample with at least one hybridization probe having a nucleic acid sequence complementary to at least a portion of the mitochondrial fusion transcript according to  claim 5 . 
     
     
         28 . A method of detecting a cancer in a mammal, the method comprising assaying a tissue sample from the mammal for the presence of at least one mitochondrial fusion transcript associated with cancer by hybridizing the sample with at least one hybridization probe having a nucleic acid sequence complementary to at least a portion of the mitochondrial fusion transcript according to 3, wherein the transcript comprises the expressed RNA transcript of a deletion sequence set out in Table 1. 
     
     
         29 . A method of detecting a cancer in a mammal, the method comprising assaying a tissue sample from the mammal for the presence of at least one aberrant mtDNA associated with cancer by hybridizing the sample with at least one hybridization probe having a nucleic acid sequence complementary to at least a portion of the mtDNA according to  claim 9 . 
     
     
         30 . The method of  claim 27 , wherein the cancer is prostate cancer, testicular cancer, ovarian cancer, breast cancer, colorectal cancer, lung cancer, melanoma skin cancer or combinations thereof. 
     
     
         31 . The method of  claim 28 , wherein the cancer is prostate cancer, testicular cancer, ovarian cancer, breast cancer, colorectal cancer, lung cancer, melanoma skin cancer or combinations thereof. 
     
     
         32 . The method of  claim 12 , wherein the cancer is prostate cancer, testicular cancer, ovarian cancer, breast cancer, colorectal cancer, lung cancer, melanoma skin cancer or combinations thereof. 
     
     
         33 . The method of  claim 29 , wherein the cancer is prostate cancer, testicular cancer, ovarian cancer, breast cancer, colorectal cancer, lung cancer, melanoma skin cancer or combinations thereof. 
     
     
         34 . A kit for conducting an assay for detecting the presence of a cancer in a mammal, said kit comprising at least one hybridization probe complementary to at least a portion of the fusion transcript of  claim 5 . 
     
     
         35 . A kit for conducting an assay for detecting the presence of a cancer in a mammal, said kit comprising at least one hybridization probe complementary to at least a portion of the fusion transcript of  claim 3 , wherein the transcript comprises the expressed RNA transcript of a deletion sequence set out in Table 1. 
     
     
         36 . A kit for conducting an assay for detecting the presence of a cancer in a mammal, said kit comprising at least one hybridization probe complementary to at least a portion of the mtDNA of  claim 9 . 
     
     
         37 . A screening tool comprised of a microarray having 10's, 100's, or 1000's of mitochondrial fusion transcripts according to  claim 5  for identification of those associated with cancer. 
     
     
         38 . A screening tool comprised of a microarray having 10's, 100's, or 1000's of mitochondrial fusion transcripts according to  claim 3  for identification of those associated with cancer, wherein the transcript comprises the expressed RNA transcript of a deletion sequence set out in Table 1. 
     
     
         39 . A screening tool comprised of a multiplexed branched DNA assay having 10's, 100's, or 1000's of mitochondrial fusion transcripts according to  claim 5  for identification of those associated with cancer. 
     
     
         40 . A screening tool comprised of a multiplexed branched DNA assay having 10's, 100's, or 1000's of mitochondrial fusion transcripts according to  claim 3  for identification of those associated with cancer, wherein the transcript comprises the expressed RNA transcript of a deletion sequence set out in Table 1.