Recurrent gene fusions in prostate cancer

• US 10,041,123 B2
• Filed: 07/06/2007
• Issued: 08/07/2018
• Est. Priority Date: 09/12/2005
• Status: Active Grant

• Current Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Chinnaiyan, Arul M., Tomlins, Scott
• Primary Examiner(s): Salmon, Katherine D
• Application Number:
  US11/825,552
• Publication Number:
  US 20090208937A1
• Time in Patent Office: 4,050 Days
• 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 in prostate cancer of androgen regulated genes or housekeeping genes and ETS family member genes are described. Compositions and methods having utility in prostate cancer diagnosis, research, and therapy are also provided.

Claims

1. An in vitro method for detecting a gene fusion in a human biological sample comprising prostate tissue, prostate cells, prostate secretions, or fractions thereof, the method comprising:

(a) forming a hybridized structure comprising;

i) a nucleic acid comprising a gene fusion, wherein said gene fusion comprises a 5′

portion fused to a 3′

portion at a fusion junction and said gene fusion is selected from the group consisting of;

(1) a transmembrane protease, serine 2 (TMPRSS2);

ETV5 gene fusion wherein the 5′

portion of the gene fusion comprises exon 1 of TMPRSS2 and the 3′

portion of the gene fusion comprises exon 2 of ETVS5;

(2) a solute carrier family 45, member 3 (SLC45A3);

ETV5 gene fusion wherein the 5′

portion of the gene fusion comprises exon 1 of SLC45A3 and the 3′

portion of the gene fusion comprises exon 8 of ETV5;

(3) a SLC45A3;

ETV1 gene fusion wherein the 5′

portion comprises exon 1 of SLC45A3 and the 3′

portion of the gene fusion comprises exon 5 of ETV1;

(4) a HERV-K_22q11.23;

ETV1 gene fusion wherein the 5′

portion comprises nucleotides 1-362 of SEQ ID NO;

421 and the 3′

portion comprises exon 5 of ETV1; and

(5) a C15ORF21;

ETV1 gene fusion wherein the 5′

portion comprises exons 1-2 of C15ORF21 and the 3′

portion of the gene fusion comprises exon 6 of ETV1; and

ii) a detectably labeled probe specifically hybridized to said nucleic acid and spanning said fusion junction; and

(b) detecting the gene fusion in the human biological sample by detecting said hybridized structure in said biological sample.

2. The method of claim 1, wherein the 5′

portion of the gene fusion further comprises a promoter region.

3. The method of claim 1, wherein the nucleic acid comprising the gene fusion is a genomic DNA.

4. The method of claim 1, wherein the nucleic acid comprising the gene fusion is a chimeric mRNA.

5. The method of claim 1, wherein the human biological sample is a sample selected from the group consisting of tissue, blood, plasma, serum, urine, urine supernatant, urine cell pellet, semen, prostatic secretions, and prostate cells.

6. The method of claim 1, wherein detecting said hybridized structure comprises using a technique selected from the group consisting of in situ hybridization (ISH), microarray, Southern blot, and northern blot.

7. The method of claim 1, wherein the nucleic acid comprising the gene fusion is produced using an amplification technique selected from the group consisting of polymerase chain reaction, reverse transcription polymerase chain reaction, transcription-mediated amplification, ligase chain reaction, strand displacement amplification, and nucleic acid sequence based amplification.

15. The method of claim 1, wherein the nucleic acid comprising the gene fusion is produced using a first amplification oligonucleotide that is complementary to the 5′

portion of the gene fusion and a second amplification oligonucleotide that is complementary to the 3′

portion of the gene fusion.

8. An in vitro method for detecting a gene fusion in a human biological sample comprising prostate tissue, prostate cells, prostate secretions, or fractions thereof, the method comprising:

(a) forming a hybridized structure comprising;

i) a nucleic acid comprising a gene fusion, wherein said gene fusion comprises a 5′

portion fused to a 3′

portion at a fusion junction, and said gene fusion is selected from the group consisting of;

(1) a TMPRSS2;

ETV5 gene fusion wherein the 5′

portion of the gene fusion comprises exon 1 of TMPRSS2 and the 3′

portion of the gene fusion comprises exon 2 of ETV5;

(2) a SLC45A3;

ETV5 gene fusion wherein the 5′

portion of the gene fusion comprises exon 1 of SLC45A3 and the 3′

portion of the gene fusion comprises exon 8 of ETVS5;

(3) a SLC45A3;

ETV1 gene fusion wherein the 5′

portion comprises exon 1 of SLC45A3 and the 3′

portion of the gene fusion comprises exon 5 of ETV1;

(4) a HERV-K_22q11.23;

ETV1 gene fusion wherein the 5′

portion comprises nucleotides 1-362 of SEQ ID NO;

421 and the 3′

portion comprises exon 5 of ETV1; and

(5) a C15ORF21;

ETV1 gene fusion wherein the 5′

portion comprises exons 1-2 of C15ORF21 and the 3′

portion of the gene fusion comprises exon 6 of ETV1; and

ii) a first detectably labeled probe specifically hybridized to the 5′

portion of the gene fusion and a second detectably labeled probe specifically hybridized to the 3′

portion of the gene fusion; and

(b) detecting the gene fusion in the human biological sample by detecting said hybridized structure in said biological sample.

9. The method of claim 8, wherein the 5′

portion of the gene fusion further comprises a promoter region.

10. The method of claim 8, wherein the nucleic acid comprising the gene fusion is a genomic DNA.

11. The method of claim 8, wherein the nucleic acid comprising the gene fusion is a chimeric mRNA.

12. The method of claim 8, wherein the human biological sample is a sample selected from the group consisting of tissue, blood, plasma, serum, urine, urine supernatant, urine cell pellet, semen, prostatic secretions, and prostate cells.

13. The method of claim 8, wherein detecting said hybridized structure comprises using in situ hybridization (ISH).

14. The method of claim 8, wherein the nucleic acid comprising the gene fusion is produced using an amplification technique selected from the group consisting of polymerase chain reaction, reverse transcription polymerase chain reaction, transcription-mediated amplification, ligase chain reaction, strand displacement amplification, and nucleic acid sequence based amplification.

16. The method of claim 8, wherein the nucleic acid comprising the gene fusion is produced using a first amplification oligonucleotide that is complementary to the 5′

portion of the gene fusion and a second amplification oligonucleotide that is complementary to the 3′

portion of the gene fusion.

17. An in vitro method for detecting a gene fusion in a human biological sample comprising prostate tissue, prostate cells, prostate secretions, or fractions thereof, the method comprising:

(a) forming a hybridized structure comprising;

i) a nucleic acid comprising a gene fusion, wherein said gene fusion comprises a 5′

portion fused to a 3′

portion at a fusion junction and said gene fusion is selected from the group consisting of;

(1) a TMPRSS2;

ETV5 gene fusion wherein the 5′

portion of the gene fusion comprises exon 1 of TMPRSS2 and the 3′

portion of the gene fusion comprises exon 2 of ETV5;

(2) a SLC45A3;

ETV5 gene fusion wherein the 5′

portion of the gene fusion comprises exon 1 of SLC45A3 and the 3′

portion of the gene fusion comprises exon 8 of ETV5;

(3) a SLC45A3;

ETV1gene fusion wherein the 5′

portion comprises exon 1 of SLC45A3 and the 3′

portion of the gene fusion comprises exon 5 of ETV1;

(4) a HERV-K_22q11.23;

ETV1 gene fusion wherein the 5′

portion comprises nucleotides 1-362 of SEQ ID NO;

421 and the 3′

portion comprises exon 5 of ETV1; and

(5) a C15ORF21;

ETV1 gene fusion wherein the 5′

portion comprises exons 1-2 of C15ORF21 and the 3′

portion of the gene fusion comprises exon 6 of ETV1; and

ii) a first amplification primer specifically hybridized to said 5′

component and a second amplification primer specifically hybridized to said 3′

component;

(b) amplifying a portion of the nucleic acid using a nucleic acid amplification reaction to produce an amplicon; and

(c) detecting the gene fusion in the human biological sample by detecting in vitro the amplicon.

18. The method of claim 17 wherein detecting the amplicon comprises hybridizing a directly labeled probe to the amplicon or use of an intercalating dye.

19. The method of claim 17 wherein the 5′

portion of the gene fusion further comprises a promoter region.

20. The method of claim 17, wherein the nucleic acid comprising the gene fusion is a genomic DNA.

21. The method of claim 17, wherein the nucleic acid comprising the gene fusion is a chimeric mRNA.

22. The method of claim 17, wherein the human biological sample is a sample selected from the group consisting of tissue, blood, plasma, serum, urine, urine supernatant, urine cell pellet, semen, prostatic secretions, and prostate cells.

23. The method of claim 17, wherein the amplification reaction is selected from the group consisting of polymerase chain reaction, reverse transcription polymerase chain reaction, transcription-mediated amplification, ligase chain reaction, strand displacement amplification, and nucleic acid sequence based amplification.