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, wherein the transcript has the nucleic acid sequence as set forth in any one of SEQ ID NOs:18 to 33 or 50. 
     
     
         2 . An isolated mitochondrial DNA (mtDNA) molecule having a nucleic acid sequence encoding the fusion transcript of  claim 1 . 
     
     
         3 . The isolated mtDNA of  claim 2 , wherein the mtDNA has the nucleic acid sequence as set forth in any one of SEQ ID NOs: 2-17 or 51. 
     
     
         4 . A mitochondrial fusion protein, wherein the fusion protein is a translation product of the fusion transcript of  claim 1 . 
     
     
         5 . The mitochondrial fusion protein of  claim 4 , wherein the fusion protein has the amino acid sequence as set forth in any one of SEQ ID NOs: 34 to 49 and 52. 
     
     
         6 . A hybridization probe having a nucleic acid sequence complementary to a portion of the mitochondrial fusion transcript of  claim 1 . 
     
     
         7 . The hybridization probe of  claim 6 , wherein the portion of the mitochondrial fusion transcript comprises an expressed sequence of mtDNA corresponding to a junction point resulting from a deletion of nucleotides of the human mtDNA genome. 
     
     
         8 . The hybridization probe of  claim 7 , wherein the probe has a length of at least about 15 nucleotides, at least about 20 nucleotides, at least about 30 nucleotides, at least about 40 nucleotides, at least about 50 nucleotides, at least about 75 nucleotides, or at least about 150 nucleotides. 
     
     
         9 . A kit for diagnosing cancer or for detecting the fusion transcript of  claim 1 , wherein the kit comprises the hybridization probe of  claim 6 . 
     
     
         10 . The kit of  claim 9 , wherein the cancer is prostate cancer, testicular cancer, ovarian cancer, breast cancer, colorectal cancer, lung cancer, melanoma skin cancer or combinations thereof. 
     
     
         11 . A method of detecting a cancer in a mammal, the method comprising assaying a tissue sample from the mammal for the presence of:
 (i) a mitochondrial fusion transcript having the nucleic acid sequence as set forth in any one of SEQ ID NOs:18 to 33 or 50;   (ii) an mtDNA molecule encoding the fusion transcript of (i);   (iii) an mtDNA molecule having the nucleic acid sequence as set forth in any one of SEQ ID NOs: 2-17 or 51;   (iv) a fusion protein comprising a translation product of the fusion transcript of (i); or   (v) a fusion protein having the amino acid sequence as set forth in any one of SEQ ID NOs: 34 to 49 and 52.   
     
     
         12 . The method of  claim 11 , wherein the method comprises hybridizing the tissue sample with at least one hybridization probe having a nucleic acid sequence complementary to at least a portion of the mitochondrial fusion transcript of (i), the mtDNA of (ii) or the mtDNA of (iii). 
     
     
         13 . The method of  claim 12 , wherein the portion of the mitochondrial fusion transcript comprises an expressed sequence of mtDNA corresponding to a junction point resulting from a deletion of nucleotides of the human mtDNA genome. 
     
     
         14 . The method of  claim 12 , 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 sequence of the mitochondrial fusion transcript or the mtDNA; and,   b) quantifying the amount of the mitochondrial fusion transcript or the mtDNA in said sample by quantifying the amount of said transcript or mtDNA hybridized to the at least one probe.   
     
     
         15 . The method of  claim 14 , wherein the step of quantifying is carried out using diagnostic imaging technology, branched DNA technology, or PCR. 
     
     
         16 . 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.