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(12) Patent Application Publication (10) Pub. No.: US 2012/0015839 A1 Chinnaiyan (43) Pub US 2012OO15839A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0015839 A1 Chinnaiyan (43) Pub. Date: Jan. 19, 2012 (54) RECURRENT GENE FUSIONS IN CANCER Related U.S. Application Data (60) Provisional application No. 61/143,598, filed on Jan. (75) Inventor: Arul M. Chinnaiyan, Plymouth, 9, 2009, provisional application No. 61/187,776, filed MI (US) on Jun. 17, 2009. (73) Assignee: THE REGENTS OF THE Publication Classification UNIVERSITY OF MICHIGAN, (51) Int. Cl. Ann Arbor, MI (US) CI2O I/68 (2006.01) C40B 30/04 (2006.01) (21) Appl. No.: 13/145,067 (52) U.S. Cl. ............................ 506/9; 435/6.14; 435/6.11 (57) ABSTRACT (22) PCT Filed: Jan. 8, 2010 The present invention relates to compositions and methods (86). PCT No.: PCT/US2O10/0205O1 for cancer diagnosis, research and therapy, including but not limited to, cancer markers. In particular, the present invention S371 (c)(1), relates to recurrent gene fusions as diagnostic markers and (2), (4) Date: Sep. 30, 2011 clinical targets for cancer (e.g., prostate cancer). & SSSSSSSSSSSSSSSSSSS s s s 8 s & S&SSSSSSS &SSS8 --------------------- :SSSSSSSSSS. Patent Application Publication Jan. 19, 2012 Sheet 1 of 32 US 2012/0015839 A1 FIGURE 1 S. SS S&SSSSSSSis sis.&Y an &SS Ssssssssssssssssssssssssssssssssssssssssssssssss Sixxxxxxxx xxxxSS&xxxxxx Patent Application Publication Jan. 19, 2012 Sheet 2 of 32 US 2012/0015839 A1 FIGURE 2 g&& S. SS ises S&S&S S&S 3. SESSSSSSSSSSSSSSS sinci: Ex888. &88& S& S&SS&S&S S&SSSSSSSSSS&S 888: 8&ss& Patent Application Publication Jan. 19, 2012 Sheet 3 of 32 US 2012/0015839 A1 FIGURE 3 Pascertase assi:3F siristecs &hsrs:Fass. Extasserticises SSR 88 (3:33:8& 3& Patent Application Publication Jan. 19, 2012 Sheet 4 of 32 US 2012/0015839 A1 FIGURE 4 Patent Application Publication Jan. 19, 2012 Sheet 5 of 32 US 2012/0015839 A1 FIGURES S. s SY Y. S&S S.SE ...--a ... SSS --- Patent Application Publication Jan. 19, 2012 Sheet 6 of 32 US 2012/0015839 A1 FIGURE 6 SS &S assass&s Patent Application Publication Jan. 19, 2012 Sheet 7 of 32 US 2012/0015839 A1 FIGURE 7 w XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXs e SSS: Patent Application Publication Jan. 19, 2012 Sheet 8 of 32 US 2012/0015839 A1 FIGURE 8 EEEI. xts. Sssss S. g;" tax SSS&SS-8 s: aw & 8&ss: S - Patent Application Publication Jan. 19, 2012 Sheet 9 of 32 US 2012/0015839 A1 FIGURE 9 Salists: S&- ; : &S 8. S8: 3: Stsi recs S Riesses: & xxxx & SS a Y - SS S. s sis & SS Patent Application Publication Jan. 19, 2012 Sheet 10 of 32 US 2012/0015839 A1 FIGURE 10 & 'SS. SSK S& Patent Application Publication Jan. 19, 2012 Sheet 11 of 32 US 2012/0015839 A1 FIGURE 11 Ssss sississssssssss S&SSS8&ss&s &- &r s N Ša isSS St. 1 & 8 sy S SS s's & S S is ...'s S &eŠ Sssss & S saw se & S &S8s S8 &:S &. kiss S SS Š SS SSS as s s were assrxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxm ex\S- Šs 8 S& S& Ssssss Sax. Patent Application Publication Jan. 19, 2012 Sheet 12 of 32 US 2012/0015839 A1 FIGURE 12 ººººººººººººººººººººººººººººº Patent Application Publication Jan. 19, 2012 Sheet 13 of 32 US 2012/0015839 A1 FIGURE 13 s ss. Ss. Ss SSS. S. s. Y s. ss gt. F. SS s S.s S i.e. Faii.22.5 r x x . s ; Fijite Sights 8& -- -- W s iss --R& S -- ES R.E.E. s N &reach. Eganax 3xx siss Nases . ess: . Nx&s Patent Application Publication Jan. 19, 2012 Sheet 14 of 32 US 2012/0015839 A1 FIGURE 13, continued SSSE38 y Sis s SS Y -- 83.3 s: rx V. XX: v. Y w x x V. v. VVxx v v. ' X w. v. Yvs . Y s Vxxx xx vx .xx vir SS. i. S is rS S SS . -. CKiy fiftete-ests S. SS F-33S F.a prešŠ s Refe: ganizatist Patent Application Publication Jan. 19, 2012 Sheet 15 of 32 US 2012/0015839 A1 FIGURE 14 Patent Application Publication Jan. 19, 2012 Sheet 18 of 32 US 2012/0015839 A1 FIGURE 17 SSSSSSY Patent Application Publication Jan. 19, 2012 Sheet 19 of 32 US 2012/0015839 A1 FIGURE 18 RSSSSSSS & Ssssssss Š s & &ssssss &c. & S& s EF-S-S83. S-S-SS: Patent Application Publication Jan. 19, 2012 Sheet 20 of 32 US 2012/0015839 A1 FIGURE 18, continued SS & Sri &N SSSS$.33SS S. S 3. Patent Application Publication Jan. 19, 2012 Sheet 21 of 32 US 2012/0015839 A1 FIGURE 19 | Patent Application Publication Jan. 19, 2012 Sheet 22 of 32 US 2012/0015839 A1 FIGURE 20 Ferrae trie Sy segate R&sky Pisitis wise £3. ----------------------------------- 8:88-8------------------------------------- . irise sailies Patent Application Publication Jan. 19, 2012 Sheet 23 of 32 US 2012/0015839 A1 FIGURE 21 ES3-33 3S. 'a's : s: s 38 S; S : S 8 an Sha -SS R s - 3833 pass Rs &sips:urctici;8&ssissile S. SS 8& 8 S S s: SS S. s SS Patent Application Publication Jan. 19, 2012 Sheet 24 of 32 US 2012/0015839 A1 FIGURE 22 Er Sigristive S.E. ..--~~~~~~~~. „~~~*~~~~. Patent Application Publication Jan. 19, 2012 Sheet 26 of 32 US 2012/0015839 A1 FIGURE 24 i. 3&SSSSSSSSSSS d S -a- F .a. --. --- SSSSS 8S ...s-S-S sci- is Šošo S$8:3SSSSSSS: SS S. Patent Application Publication Jan. 19, 2012 Sheet 27 of 32 US 2012/0015839 A1 FIGURE 25 8&seiving multiple mappiricas s: Red K& false positive inappigs sississ-s:x: &xis&SY is, SE3: S388. S3RSSS383&S:3888SSS $3:S3. Sists airs sp3ssis3fai::$wsk:8: 3:38. S&ssiss's ess&ssissi:sigis Strids.r. 8 Wr Rears sai i is fissi; auriday fest sited ix} is siddie feati Patent Application Publication Jan. 19, 2012 Sheet 28 of 32 US 2012/0015839 A1 FIGURE 26 Re-- - - - - - - - - - - - - - Fue-- - - - - - - - - $8 - - - - - - - - - - - - SSR 883& Risics&Si3Rf; if: &$33.33: Fisii:Sicilitic: w Y -- - as --- :-83 3-3,888. R&ssasssssssss R&ssissatists Patent Application Publication Jan. 19, 2012 Sheet 29 of 32 US 2012/0015839 A1 FIGURE 27 s Sr. scississ&xis S. i. six-war in Si: y - 88&ssssssss & -x ... &: ::::::::: ::::::::: ls xx X. w 3Sssssssssss - C s 8: x-3X SXP-3 Waxxxx xx www Patent Application Publication Jan. 19, 2012 Sheet 30 of 32 US 2012/0015839 A1 FIGURE 28 A l S&S SS: s assssssssss-r S-s-s -- ises amasamsix syse, estas its se-so sixxxx a xiii SSSSSS 3. is S. sa III.Y-Y - ^. Patent Application Publication Jan. 19, 2012 Sheet 31 of 32 US 2012/0015839 A1 FIGURE 29 SSSSS s s xxx sea r Xauxxxxx ass sw: 8xxx xxxx SSSSSSS xx s: xxxxx SS css SXX-XXXX s XS 'ss. s xxx XX XX XX s ex-heasy: 83. :SS s&s-chssists:: 3-ississ&as s.S. YT. &sisis. iss-skis&s: re-his fixxi. shayy: 3. RSSS 3 3-chi: Patent Application Publication Jan. 19, 2012 Sheet 32 of 32 US 2012/0015839 A1 FIGURE 30 &SSS38 ?. ? US 2012/0015839 A1 Jan. 19, 2012 RECURRENT GENE FUSIONS IN CANCER (2005)). Thus, identifying recurrent gene rearrangements in common epithelial tumors may have profound implications CROSS REFERENCE TO RELATED for cancer drug discovery efforts as well as patient treatment. APPLICATIONS 0001. This application claims priority to U.S. provisional SUMMARY OF THE INVENTION applications 61/143,598, filed Jan. 9, 2009 and 61/187,776, 0006. The present invention relates to compositions and filed Jun. 17, 2009, each of which is herein incorporated by methods for cancer diagnosis, researchand therapy, including reference in its entirety. but not limited to, cancer markers. In particular, the present invention relates to recurrent gene fusions as diagnostic GOVERNMENT SUPPORT markers and clinical targets for cancer (e.g., prostate cancer). 0002 This invention was made with government support 0007 For example, in some embodiments, the present undergrant numbers CA069568, CA 111275 awarded by the invention provides a method for identifying prostate cancer in National Institutes of Health and grant number W81XWH a patient comprising: providing a sample from the patient; 08-1-0031 awarded by the Army. The government has certain and detecting the presence or absence in the sample of a gene rights in the invention. fusion having a 5" portion from a transcriptional regulatory region of an SLC45A3 gene and a 3' portion from an ELK4 FIELD OF THE INVENTION gene, wherein detecting the presence in the sample of the gene fusion identifies prostate cancer in the patient. In some 0003. The present invention relates to compositions and embodiments, the transcriptional regulatory region of the methods for cancer diagnosis, research and therapy, including SLC45A3 gene comprises a promoter region of the SLC45A3 but not limited to, cancer markers. In particular, the present gene. In some embodiments, the detecting comprises detect invention relates to recurrent gene fusions as diagnostic ing chimeric mRNA transcripts having a 5' RNA portion markers and clinical targets for cancer (e.g., prostate cancer). transcribed from the transcriptional regulatory region of the SLC45A3 gene and a 3' RNA portion transcribed from the BACKGROUND OF THE INVENTION ELK4 gene. In some embodiments, the gene fusion is a read 0004. A central aim in cancer research is to identify altered through transcript. In some embodiments, the sample is tis genes that are causally implicated in oncogenesis. Several Sue, blood, plasma, serum, urine, urine Supernatant, urine cell types of Somatic mutations have been identified including pellet, semen, prostatic secretions or prostate cells.
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