Recurrent gene fusions in prostate cancer

• US 9,745,635 B2
• Filed: 09/24/2015
• Issued: 08/29/2017
• 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
• Application Number:
  US14/864,466
• Publication Number:
  US 20160097104A1
• Time in Patent Office: 705 Days
• Field of Search: 435 611, 435 612, 435 912
• 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 hybridized oligonucleotide:

target gene fusion duplex, wherein the target gene fusion comprises a chimeric nucleic acid molecule in which a 5′

portion of the chimeric nucleic acid molecule is from a TMPRSS2 gene and a 3′

portion of the chimeric nucleic acid molecule is 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; and

wherein the oligonucleotide is covalently labeled with a detectable label.

2. The composition of claim 1 wherein the ETS family member gene is an ERG gene.

3. The composition of claim 1 wherein the ETS family member gene is an ETV1 gene.

4. The composition of claim 1 wherein the ETS family member gene is an ETV4 gene.

5. The composition of claim 1 wherein the ETS family member gene is an FLI1 gene.

6. The composition of claim 1 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.

7. The composition of claim 1 wherein the 5′

portion of the chimeric nucleic acid molecule is from a transcriptional regulatory region of the TMPRSS2 gene.

8. The composition of claim 1 wherein the transcriptional regulatory region comprises a promoter region of the TMPRSS2 gene.

9. The composition of claim 1 wherein the oligonucleotide is hybridized to a junction at which the 5′

portion of the chimeric nucleic acid molecule is fused to the 3′

portion of the chimeric nucleic acid molecule.

10. The composition of claim 1 wherein:

a) the oligonucleotide is hybridized to the 5′

portion of the chimeric nucleic acid molecule and the composition further comprises a second oligonucleotide hybridized to the 3′

portion of the chimeric nucleic acid molecule;

or

b) the oligonucleotide is hybridized to the 3′

portion of the chimeric nucleic acid molecule and the composition further comprises a second oligonucleotide hybridized to the 5′

portion of the chimeric nucleic acid molecule, wherein the second oligonucleotide is covalently labeled with a detectable label.

11. The composition of claim 10 further comprising a polymerase.

12. The composition of claim 10 further comprising a third oligonucleotide covalently labeled with a detectable label.

13. The composition of claim 1 further comprising a detectably labeled oligonucleotide probe that hybridizes to a nucleic acid molecule selected from one or more of the group consisting of PCA3, PSA, AMACR/P504S, PCGEM1, prostein/P501S, P503S, P504S, P509S, P510S, prostase/P703P, and P710P.

14. The composition of claim 1 further comprising a detectably labeled oligonucleotide probe that hybridizes to PSA.

15. The composition of claim 1 further comprising a detectably labeled oligonucleotide probe that hybridizes to PCA3.

16. A method of producing a hybridized oligonucleotide:

target gene fusion duplex, the method comprising contacting a sample comprising a target gene fusion comprising a chimeric nucleic acid molecule in which a 5′

portion of the chimeric nucleic acid molecule is from a TMPRSS2 gene and a 3′

portion of the chimeric nucleic acid molecule is from an ETS family member gene with an oligonucleotide covalently labeled with a detectable label and having a sequence that hybridizes to a junction at which the 5′

portion of the chimeric nucleic acid molecule is fused to the 3′

portion of the chimeric nucleic acid molecule.

17. The method of claim 16 wherein the 5′

portion of the chimeric nucleic acid molecule is from a TMPRSS2 gene and the 3′

portion of the chimeric nucleic acid molecule is 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.

18. The method of claim 16 wherein the sample comprises tissue, blood, urine, semen, prostatic secretion, plasma, serum, urine supernatant, urine cell pellet, or a prostate cell.