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Use of Microvesicles in Analyzing Nucleic Acid Profiles

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Use of Microvesicles in Analyzing Nucleic Acid Profiles (19) TZZ _T (11) EP 2 475 988 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12Q 1/6886 (2018.01) C12Q 1/6809 (2018.01) 14.11.2018 Bulletin 2018/46 C12Q 1/6806 (2018.01) (21) Application number: 10816090.4 (86) International application number: PCT/US2010/048293 (22) Date of filing: 09.09.2010 (87) International publication number: WO 2011/031877 (17.03.2011 Gazette 2011/11) (54) USE OF MICROVESICLES IN ANALYZING NUCLEIC ACID PROFILES VERWENDUNG VON MIKROVESIKELN BEI DER ANALYSE VON NUKLEINSÄUREPROFILEN UTILISATION DE MICROVÉSICULES DANS L’ANALYSE DE PROFILS D’ACIDE NUCLÉIQUE (84) Designated Contracting States: US-A1- 2005 003 426 US-A1- 2008 268 429 AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • SKOG JOHAN ET AL: "Glioblastoma PL PT RO SE SI SK SM TR microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic (30) Priority: 09.09.2009 US 241014 P biomarkers", NATURE CELL BIOLOGY, MACMILLAN MAGAZINES LTD, vol. 10, no. 12, 1 (43) Date of publication of application: December 2008 (2008-12-01), pages 1470-1476, 18.07.2012 Bulletin 2012/29 XP002526160, ISSN: 1465-7392, DOI: 10.1038/NCB1800 [retrieved on 2008-11-16] (60) Divisional application: • TAYLOR D D ET AL: "MicroRNA signatures of 18199345.2 tumor-derived exosomes as diagnostic biomarkers of ovarian cancer", GYNECOLOGIC (73) Proprietor: The General Hospital Corporation ONCOLOGY, ACADEMIC PRESS, LONDON, GB, Boston, MA 02114 (US) vol. 110, no. 1, 1 July 2008 (2008-07-01), pages 13-21, XP022795052, ISSN: 0090-8258, DOI: (72) Inventors: 10.1016/J.YGYNO.2008.04.033 [retrieved on • NOERHOLM, Mikkel 2008-06-25] D-82131 Gauting (DE) • NILSSONJ ET AL: "Prostate cancer-derived urine • SKOG, Johan, Karl, Olov exosomes: a novel approach to biomarkers for New York, NY 10069 (US) prostate cancer", BRITISH JOURNAL OF • BREAKEFIELD, Xandra, O. CANCER,HARCOURT PUBLISHERS, vol. 100, no. Newton, MA 02459 (US) 10, 1 May 2009 (2009-05-01), pages 1603-1607, • CARTER, Bob XP008149487, ISSN: 0007-0920, DOI: San Diego, CA 92130 (US) 10.1038/SJ.BJC.6605058 [retrieved on 2009-04-28] (74) Representative: Kehoe, Laura Ellen et al • MIRANDA K C ET AL: "Nucleic acids within Keltie LLP urinary exosomes/microvesicles are potential No.1 London Bridge biomarkers for renal disease", KIDNEY London SE1 9BA (GB) INTERNATIONAL, NATURE PUBLISHING GROUP, NEW YORK, vol. 78, no. 2, 1 July 2010 (56) References cited: (2010-07-01), pages191-199, XP002686137, ISSN: WO-A1-2009/100029 WO-A1-2011/009104 1523-1755,DOI: 10.1038/KI.2010.106 [retrieved on WO-A1-2011/127219 WO-A2-2005/121369 2010-04-28] WO-A2-2008/104543 WO-A2-2009/155505 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 475 988 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 475 988 B1 • MIKKEL NOERHOLM ET AL: "RNA expression patterns in serum microvesicles from patients withglioblastoma multiforme and controls", BMC CANCER, BIOMED CENTRAL, LONDON, GB, vol. 12, no. 1, 17 January 2012 (2012-01-17), page 22, XP021118100, ISSN: 1471-2407, DOI: 10.1186/1471-2407-12-22 2 EP 2 475 988 B1 Description FIELD OF INVENTION 5 [0001] The present invention relates to the general fields of nucleic acid analysis in human or other animal subjects, particularly the profiling of nucleic acids from a biological sample, and in particular, from microvesicles. BACKGROUND 10 [0002] Cancer molecular diagnostics is becoming increasingly important with the accumulating knowledge of the molecular mechanisms underlying various types of cancers and the implications for diagnosis, treatment selection and prognosis. [0003] Various molecular diagnostic tests like mutational analysis, methylation status of genomic DNA and gene expression analysis are currently being used to answer clinical questions. Differential gene expression analysis of cancer 15 cells has so far primarily been done on cancer cells derived from surgically removed tumor tissue or from tissue obtained by biopsy. However, the ability to profile gene expression using a blood sample from a cancer patient rather than a tissue sample is desirable because a non-invasive approach such as this has wide ranging implications in terms of patient welfare, the ability to conduct longitudinal disease monitoring, and the ability to obtain expression profiles even when tissue cells are not easily accessible, e.g., in ovarian or brain cancer patients. 20 [0004] So far, gene expression profiling using a blood sample is confined to analyzing RNA extracted from Peripheral Blood Mononuclear Cells (PBMC) (Hakonarson et al., 2005) or Circulating Tumor Cells (CTC) (Cristofanilli and Mendel- sohn, 2006). WO2009/100029 discloses the analysis of miRNA and mRNA expression from glioblastoma patients and mention that mRNA profiles obtained from microvesicles may be used in the prognosis and diagnosis of cancer. This invention discloses a novel method of profiling gene expressions and provides novel gene expression signatures asso- 25 ciated with diseases by analyzing nucleic acids extracted from microvesicles from a bodily fluid, e.g., a blood sample. BRIEF SUMMARY OF THE INVENTION [0005] The present invention provides a method of aiding diagnosis, prognosis or therapy treatment planning for a 30 subject, comprising: a. isolating microvesicles from a subject; b. measuring the expression level of one or more RNA transcripts extracted from the isolated microvesicles; c. determining a profile of the one or more RNA transcripts based on the expression level; and 35 d. comparing the profile to a reference profile to aid diagnosis, prognosis or therapy treatment planning for the subject, wherein the one or more RNA transcripts comprise each of the transcripts in Table 1. [0006] Described herein are genetic profiles associated with biological conditions and methods of applying these profiles in evaluating the biological conditions. Described herein is a profile of one or more RNA transcripts obtained 40 from micro vesicles. Described herein is that the one or more RNA transcripts may be selected from those listed in Tables 1-20. The microvesicles from which the profile is obtained may be isolated from a bodily fluid from a subject. The bodily fluid may be blood, serum, plasma or urine. The subject may be a human subject. The human subject may be a brain cancer patient such as a glioblastoma patient. [0007] The profile may be obtained through analyzing RNA transcripts obtained from microvesicles. The analysis of 45 RNA transcripts may be performed by a method such as microarray analysis, Reverse Transcription PCR, Quantitative PCR or a combination of these above methods. The analysis may include an additional step of data analysis. The data analysis can be accomplished with Clustering Analysis, Principle Component Analysis, Linear Discriminant Analysis, Receiver Operating Characteristic Curve Analysis, Binary Analysis, Cox Proportional Hazards Analysis, Support Vector Machines and Recursive Feature Elimination (SVM-RFE), Classification to Nearest Centroid, Evidence-based Analysis, 50 or a combination of the above methods. The profile from microvesicles is a profile of each of the RNA transcripts listed in Table 1. [0008] Also described herein, but outside the scope of the claimed invention, is a method of aiding diagnosis, prognosis or therapy treatment planning for a subject, comprising the steps of: a) isolating microvesicles from a subject; b) measuring the expression level of one or more RNA transcripts extracted from the isolated microvesicles; c) determining a profile 55 of the one or more RNA transcripts based on the expression level; and d) comparing the profile to a reference profile to aid diagnosis, prognosis or therapy treatment planning for the subject. The microvesicles used in the method may be isolated from a bodily fluid from the subject. The bodily fluid may be blood, serum, plasma or urine. The subject may be a human subject. The human subject may be a brain cancer patient such as a glioblastoma patient. The step (b) in the 3 EP 2 475 988 B1 method may be accomplished with a microarray analysis, Reverse Transcription PCR, Quantitative PCR or a combination of the above methods. The step (c) in the method may include an additional step of data analysis. The data analysis can be accomplished with Clustering Analysis, Principle Component Analysis, Linear Discriminant Analysis, Receiver Operating Characteristic Curve Analysis, Binary Analysis, Cox Proportional Hazards Analysis, Support Vector Machines 5 and Recursive Feature Elimination (SVM-RFE), Classification to Nearest Centroid, Evidence-based Analysis, or a com- bination of the above methods. The RNA transcripts whose profiles are determined may be one or more RNA transcripts selected from those listed in Tables 1-20. The RNA transcripts whose profiles are determined may include one or more RNA transcripts selected from any one of the Tables 1-20. The RNA transcripts may be all of the transcripts listed in any one of Tables 2-20. 10 [0009] Further described herein, but outside the scope of the claimed invention, is a method of preparing a personalized genetic profile report for a subject, comprising the steps of: (a) isolating microvesicles from a subject; (b) detecting or measuring one or more genetic aberrations within the isolated microvesicles; (c) determining one or more genetic profiles from the data obtained from steps (a) and (b); (d) optionally comparing the one or more genetic profiles to one or more reference profiles; and (e) creating a report summarizing the data obtained from steps (a) through (d) and optionally 15 including diagnostic, prognostic or therapeutic treatment information.
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