Recurrent gene fusions in prostate cancer

• US 8,211,645 B2
• Filed: 12/30/2009
• Issued: 07/03/2012
• Est. Priority Date: 09/12/2005
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated
• Original Assignee: Brigham and Women's Hospital Incorporated, Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Tomlins, Scott, Rhodes, Daniel, Chinnaiyan, Arul, Mehra, Rohit, Rubin, Mark A., Sun, Xiao-Wei, Perner, Sven, Lee, Charles, Demichelis, Francesca
• Primary Examiner(s): Horlick, Kenneth R.
• Assistant Examiner(s): Tung, Joyce
• Application Number:
  US12/650,164
• Publication Number:
  US 20110034677A1
• Time in Patent Office: 916 Days
• Field of Search: 536/22.1, 536/24.3, 435/6.12, 435/91.2, 435/810
• US Class Current: 435/6.12
• CPC Class Codes: A01K 2217/072 maintaining or altering function, i.e. knock in
• CPC Class Codes: A01K 2217/206 Animal model comprising tissue-specific expression system, e.g. tissue specific expression of transgene, of Cre recombinase
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/0331 Animal model for proliferative diseases
• CPC Class Codes: A01K 67/0275 Genetically modified vertebrates, e.g. transgenic
• CPC Class Codes: C07K 14/82 Translation products from oncogenes
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 9/6424 Serine endopeptidases (3.4.21)
• CPC Class Codes: C12N 9/6445 Kallikreins (3.4.21.34; 3.4.21.35)
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/112 Disease subtyping, staging or classification
• CPC Class Codes: C12Q 2600/118 Prognosis of disease development
• CPC Class Codes: C12Q 2600/136 Screening for pharmacological compounds
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: G01N 33/57434 of prostate
• CPC Class Codes: Y10S 435/81 : Packaged device or kit

Abstract

Recurrent gene fusions of androgen regulated genes and ETS family member genes in prostate cancer are described. Compositions and methods having utility in prostate cancer diagnosis, research, and therapy are also provided.

Claims

1. A composition comprising a first oligonucleotide probe comprising a sequence that hybridizes to a 5′

portion of a chimeric DNA or chimeric mRNA from a transcriptional regulatory region of an androgen regulated gene, wherein the androgen regulated gene is selected from the group consisting of TMPRSS2 and PSA, and a second oligonucleotide probe comprising a sequence that hybridizes to a 3′

portion of the chimeric DNA or chimeric mRNA from an ETS family member gene, wherein the ETS family member gene is selected from the group consisting of ERG, ETV1 (ER81), FLI1, ETS1, ETS2, ELK1, ETV6 (TEL1), ETV7 (TEL2), GABPα

, ELF1, ETV4 (E1AF;

PEA3), ETV5 (ERM), ERF, PEA3/E1AF, PU.1, ESE1/ESX, SAP1 (ELK4), ETV3 (METS), EWS/FLI1, ESE1, ESE2 (ELF5), ESE3, PDEF, NET (ELK3;

SAP2), NERF (ELF2), and FEV.

2. The composition of claim 1 wherein the androgen regulated gene is selected from the group consisting of TMPRSS2 and PSA and the ETS family member gene is selected from the group consisting of ERG, ETV1, and ETV4.

3. The composition of claim 1 wherein the androgen regulated gene is TMPRSS2 and the ETS family member gene is an ERG gene.

4. The composition of claim 1 wherein the chimeric DNA or chimeric mRNA is obtained from a tissue, blood, urine, semen, prostatic secretion, plasma, serum, urine supernatant, urine cell pellet, or prostate cell sample.

5. The composition of claim 1 wherein the composition comprises an in situ hybridization probe for detecting a deletion or rearrangement associated with a fusion of the androgen regulated gene with the ETS family member gene.

6. A kit comprising one or more composition of claim 1.

7. The kit of claim 5 comprising one or more composition selected from the group consisting of

a) a first labeled probe having an oligonucleotide sequence that hybridizes to a transcriptional regulatory region of a TMPRSS2 gene and a second labeled probe having an oligonucleotide sequence that hybridizes to an ERG gene;

b) a first labeled probe having an oligonucleotide sequence that hybridizes to a transcriptional regulatory region of a TMPRSS2 gene and a second labeled probe having an oligonucleotide sequence that hybridizes to an ETV1 gene; and

c) a first labeled probe having an oligonucleotide sequence that hybridizes to a transcriptional regulatory region of a TMPRSS2 gene and a second labeled probe having an oligonucleotide sequence that hybridizes to an ETV4 gene.

8. A composition comprising a first amplification oligonucleotide comprising a sequence that hybridizes to a 5′

portion of a chimeric DNA or chimeric mRNA from a transcriptional regulatory region of an androgen regulated gene, wherein the androgen regulated gene is selected from the group consisting of TMPRSS2 and PSA, and a second amplification oligonucleotide comprising a sequence that hybridizes to a 3′

portion of the chimeric DNA or chimeric mRNA from an ETS family member gene, wherein the ETS family member gene is selected from the group consisting of ERG, ETV1 (ER81), FLI1, ETS1, ETS2, ELK1, ETV6 (TEL1), ETV7 (TEL2), GABPα

, ELF1, ETV4 (E1AF;

PEA3), ETV5 (ERM), ERF, PEA3/E1AF, PU.1, ESE1/ESX, SAP1 (ELK4), ETV3 (METS), EWS/FLI1, ESE1, ESE2 (ELF5), ESE3, PDEF, NET (ELK3;

SAP2), NERF (ELF2), and FEV.

9. The composition of claim 8 wherein the androgen regulated gene comprises TMPRSS2 or PSA, and the ETS family member gene comprises ERG, ETV1, or ETV4.

10. The composition of claim 8, wherein the androgen regulated gene is TMPRSS2 and the ETS family member gene is an ERG gene.

11. The composition of claim 8, wherein the chimeric DNA or chimeric mRNA is obtained from a tissue blood, urine, semen, prostatic secretion, plasma, serum, urine supernatant, urine cell pellet, or prostate cell sample.

12. A kit comprising one or more composition of claim 8.

13. The kit of claim 12 comprising one or more composition selected from the group consisting of

a) a first amplification oligonucleotide having a sequence that hybridizes to a transcriptional regulatory region of a TMPRSS2 gene, and a second amplification oligonucleotide having a sequence that hybridizes to an ERG gene;

b) a first amplification oligonucleotide having a sequence that hybridizes to a transcriptional regulatory region of a TMPRSS2 gene, and a second amplification oligonucleotide having a sequence that hybridizes to an ETV1 gene; and

c) a first amplification oligonucleotide having a sequence that hybridizes to a transcriptional regulatory region of a TMPRSS2 gene, and a second amplification oligonucleotide having a sequence that hybridizes to an ETV4 gene.

14. A composition comprising a hybridized oligonucleotide:

target gene fusion DNA or RNA duplex, wherein the target gene fusion comprises a fusion of a TMPRSS2 or a PSA gene with an ERG, an ETV1, or an ETV4 gene, wherein the oligonucleotide is hybridized to a 5′

portion of a chimeric DNA or chimeric mRNA from a transcriptional regulatory region of the TMPRSS2 or the PSA gene, or it is hybridized to a 3′

portion of the chimeric DNA or chimeric mRNA from gene the ERG, the ETV1, or the ETV4 gene, and wherein the target gene fusion is obtained from a tissue, blood, urine, semen, prostatic secretion, plasma, serum, urine supernatant, urine cell pellet, or prostate cell sample.

15. The composition of claim 14 wherein the target gene fusion comprises a fusion of a TMPRSS2 gene with an ERG gene.

16. The composition of claim 14 wherein the hybridized oligonucleotide is a probe.

17. The composition of claim 14 wherein the hybridized oligonucleotide is an amplification oligonucleotide.