Recurrent gene fusions in prostate cancer

• US 10,190,173 B2
• Filed: 05/09/2016
• Issued: 01/29/2019
• 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:
  US15/149,780
• Publication Number:
  US 20160319369A1
• Time in Patent Office: 995 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 fluorescence in situ hybridization (FISH) method for detecting an ARG-ETS gene fusion in a sample from a subject, the method comprising:

(a) hybridizing a directly labeled FISH probe to an ARG-ETS gene fusion comprising a 5′

portion fused to a 3′

portion, said 5′

portion from an ARG gene selected from the group consisting of PSA and TMPRSS2 and said 3′

portion from an ETS family member gene 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

(b) detecting the presence of the ARG-ETS gene fusion in the sample from the subject by detecting hybridization of the directly labeled FISH probe to a junction at which the 5′

portion of the gene fusion fuses to the 3′

portion of the gene fusion.

2. The FISH method of claim 1 wherein the ETS gene is ERG.

3. The FISH method of claim 1 wherein the ARG is TMPRSS2.

4. The FISH method of claim 1 wherein the ARG-ETS gene fusion comprises exon 4 of ERG, exon 2 of ERG, and/or exon 1 of TMPRSS2.

5. A FISH method for detecting an ARG-ETS gene fusion in a sample from a subject, the method comprising:

(a) hybridizing a first directly labeled FISH probe and a second directly labeled FISH probe to an ARG-ETS gene fusion comprising a 5′

portion fused to a 3′

portion, said 5′

portion from an ARG gene selected from the group consisting of PSA and TMPRSS2 and said 3′

portion from an ETS family member gene 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

(b) detecting the presence of the ARG-ETS gene fusion in the sample from the subject by detecting hybridization of the first directly labeled FISH probe to the 5′

portion of the gene fusion and detecting hybridization of the second directly labeled FISH probe to the 3′

portion of the gene fusion.

6. The FISH method of claim 5 wherein the ETS gene is ERG.

7. The FISH method of claim 5 wherein the ARG is TMPRSS2.

8. A composition for FISH analysis of a sample from a subject, the composition comprising a directly labeled FISH probe comprising a sequence capable of hybridizing to a fusion junction of an ARG-ETS gene fusion, wherein said ARG-ETS gene fusion comprises a 5′

portion fused to a 3′

portion, said 5′

portion is from an ARG gene selected from the group consisting of PSA and TMPRSS2, and said 3′

portion is from an ETS family member gene selected from the group consisting of ERG, ETV1 (ER81), FLIT, 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 ETS gene is ERG.

10. The composition of claim 8 wherein the ARG is TMPRSS2.

11. A composition for FISH analysis of a sample from a subject, the composition comprising a first directly labeled FISH probe capable of hybridizing to a 5′

portion of an ARG-ETS gene fusion and a second directly labeled FISH probe capable of hybridizing to the 3′

portion of the ARG-ETS gene fusion, wherein said ARG-ETS gene fusion comprises a 5′

portion fused to a 3′

portion, said 5′

portion is from an ARG gene selected from the group consisting of PSA and TMPRSS2, and said 3′

portion is from an ETS family member gene 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.

12. The composition of claim 11 wherein the ETS gene is ERG.

13. The composition of claim 11 wherein the ARG is TMPRSS2.

14. A kit for FISH analysis of a sample from a subject, the kit comprising a directly labeled FISH probe comprising a sequence capable of hybridizing to a fusion junction of an ARG-ETS gene fusion, wherein said ARG-ETS gene fusion comprises a 5′

portion fused to a 3′

portion, said 5′

portion is from an ARG gene selected from the group consisting of PSA and TMPRSS2, and said 3′

portion is from an ETS family member gene 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.

15. A kit for FISH analysis of a sample from a subject, the kit comprising a first directly labeled FISH probe capable of hybridizing to a 5′

portion of an ARG-ETS gene fusion and a second directly labeled FISH probe capable of hybridizing to the 3′

portion of the ARG-ETS gene fusion, wherein said ARG-ETS gene fusion comprises a 5′

portion fused to a 3′

portion, said 5′

portion is from an ARG gene selected from the group consisting of PSA and TMPRSS2, and said 3′

portion is from an ETS family member gene 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.

16. A system for FISH analysis of a sample from a subject, the system comprising:

a) one or more probe sets that comprise;

i) a directly labeled FISH probe comprising a sequence capable of hybridizing to a fusion junction of an ARG-ETS gene fusion, wherein said ARG-ETS gene fusion comprises a 5′

portion fused to a 3′

portion, said 5′

portion is from an ARG gene selected from the group consisting of PSA and TMPRSS2, and said 3′

portion is from an ETS family member gene 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;

or

ii) a first directly labeled FISH probe capable of hybridizing to a 5′

portion of an ARG-ETS gene fusion and a second directly labeled FISH probe capable of hybridizing to the 3′

portion of the ARG-ETS gene fusion, wherein said ARG-ETS gene fusion comprises a 5′

portion fused to a 3′

portion, said 5′

portion is from an ARG gene selected from the group consisting of PSA and TMPRSS2, and said 3′

portion is from an ETS family member gene 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

b) a means for detecting directly labeled FISH probes in the sample.