Methods of diagnosing and treating prostate cancer characterized by NDRG1-ERG fusion
An in depth analysis of prostate cancer prostatectomy samples which over-express the ERG oncogene led to the discovery of a novel gene translocation in prostate cancer, between the NDRG1 gene (N-myc downstream regulated gene 1) on chromosome 8 and the ERG oncogene on chromosome 21, leading to the expression of a chimeric NDRG1-ERG protein. Methods and compositions useful for diagnosing and treating prostate cancer characterized by NDRG1-ERG fusion are described.
1. A method comprising providing a biological sample from a patient and detecting the presence of an NDRG1-ERG fusion molecule comprising a 5′ portion of the NDRG1 gene and a ′3 portion of the ERG gene in said sample, wherein the NDRG1-ERG fusion molecule being detected is a genomic fusion molecule on a chromosome comprising a 5′ portion of the NDRG1 gene and a ′3 portion of the ERG gene, wherein the 5′ portion of the NDRG1 gene includes a portion of the 5′ transcription regulatory region of the NDRG1 gene, wherein the genomic fusion molecule is detected by fluorescence in situ hybridization (FISH) assay selected from the group consisting of
a) a FISH assay that detects translocation of NRGD1 using a pair of break-apart probes flanking the NDRG1 gene, wherein one probe is specific for a region on the centromeric side of the NDRG1 gene, and the other probe is specific for a region on the telomeric side of the NDRG1 gene, and
b) a FISH assay that detects chromosomal rearrangement which creates an NDRG1-ERG fusion, wherein one probe is specific for the upstream chromosomal region of the NDRG1 gene, and the other probe is specific for the downstream chromosomal region of the ERG gene.
2. The method of claim 1 , wherein the FISH assay is performed using a pair of break-apart probes flanking the NDRG1 gene, wherein one probe is specific for a region on the centromeric side of the NDRG1 gene, and the other probe is specific for a region on the telomeric side of the NDRG1 gene.
3. The method of claim 1 , wherein the FISH assay is performed using a pair of probes that detect chromosomal rearrangement which creates an NDRG1-ERG fusion, wherein one probe is specific for the upstream chromosomal region of the NDRG1 gene, and the other probe is specific for the downstream chromosomal region of the ERG gene.
4. The method of claim 1 , wherein the nucleic acid probes of (a) comprise BAC clones designated as RP11-185E14 and RP11-1145H17.
5. The method of claim 1 , wherein nucleic acid probes of (b) comprise BAC clones designated as RP11-1145H17 and RP11-24A11.
6. A method comprising providing a biological sample from a patient and detecting the presence of an NDRG1-ERG fusion molecule comprising a 5′ portion of the NDRG1 gene and a ′3 portion of the ERG gene in said sample, wherein the NDRG1-ERG fusion molecule being detected is a fusion mRNA molecule comprising a 5′ portion of an NDRG1 mRNA and a ′3 portion of an ERG mRNA, wherein the NDRG1-ERG fusion molecule is detected by using a nucleic acid amplification method, using a first primer specific for a 5′ region of an NDRG1 mRNA, and a second primer specific for a 3′ region of an ERG mRNA wherein said fusion mRNA molecule is encoded by a cDNA comprising the nucleotide sequence of SEQ ID NO: 6 or SEQ ID NO: 8.
7. The method of claim 6 , wherein the nucleic acid amplification method selected from the group consisting of polymerase chain reaction (PCR), and reverse transcription polymerase chain reaction (RT-PCR).
8. The method of claim 6 , wherein said 5′ region of the NDRG1 mRNA comprises the 5′ untranslated region, exon 1, exon 2 and exon 3 of the NDRG1 mRNA.
9. The method of claim 8 , wherein said first primer hybridizes to at least one of the 5′ untranslated region or exon 1 of the NDRG1 mRNA.
10. The method of claim 6 , wherein said 3′ region of the ERG mRNA comprises the 3′ untranslated region, exon 4 and exons downstream of exon 4.
11. The method of claim 6 , wherein the nucleic acid amplification method is performed using primers comprising at least a primer specific for the junction of said fusion mRNA, wherein said junction comprises the sequence as set forth in SEQ ID NO: 4 or 5.
12. The method of claim 6 , wherein said 5′ region of the NDRG1 mRNA comprises the 5′ untranslated region and exon 1 of the NDRG1 mRNA.
13. The method of claim 12 , wherein said first primer hybridizes to at least one of the 5′ untranslated region or exon 1 of the NDRG1 mRNA.
14. A method comprising providing a biological sample from a patient and detecting the presence of an NDRG1-ERG fusion molecule comprising a 5′ portion of the NDRG1 gene and a ′3 portion of the ERG gene in said sample, wherein the NDRG1-ERG fusion molecule being detected is a fusion mRNA molecule comprising a 5′ portion of an NDRG1 mRNA and a ′3 portion of an ERG mRNA, wherein the NDRG1-ERG fusion molecule is detected by using a hybridization method selected from the group consisting of in situ hybridization, hybridization to a microarray, solution phase hybridization, and Northern blot hybridization wherein the hybridization method is performed using an oligonucleotide probe specific for the junction of said fusion mRNA, wherein said junction comprises the sequence as set forth in SEQ ID NO: 4 or 5.
15. The method of claims 1 , 6 , or 14 , wherein said sample is selected from the group consisting of prostate tissue, prostate cells, blood, urine, semen, and prostatic secretions.