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(12) Patent Application Publication (10) Pub. No.: US 2016/0251718A1 Giudice Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0251718A1 Giudice Et Al US 2016025 1718A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0251718A1 Giudice et al. (43) Pub. Date: Sep. 1, 2016 (54) ENDOMETROSS CLASSIFIER Publication Classification (71) Applicant: THE REGENTS OF THE (51) Int. Cl. UNIVERSITY OF CALIFORNLA, CI2O I/68 (2006.01) Oakland, CA (US) (52) U.S. Cl. (72) Inventors: Linda C. Giudice, Los Altos Hills, CA CPC ........ CI2O I/6883 (2013.01); C12O 2600/1 12 (US); Juan C. Irwin, El Cerrito, CA (2013.01); C12O 2600/158 (2013.01) (US); John S. Tamaresis, Redwood City, CA (US) (57) ABSTRACT (21) Appl. No.: 15/026,582 (22) PCT Fled: Sep. 30, 2014 The present disclosure provides methods and compositions that are useful for diagnosing the presence or absence of (86) PCT NO.: PCT/US2O14/0583.38 endometriosis and the severity of endometriosis in a Subject. S371 (c)(1), The methods and compositions are also useful for distin (2) Date: Mar. 31, 2016 guishing endometriosis from other uterine or pelvic patholo gies in a Subject. Also described are sets of genes whose Related U.S. Application Data expression levels in a biological sample are diagnostic for (60) Provisional application No. 61/885,284, filed on Oct. endometriosis, and compositions useful for diagnosis, prog 1, 2013. nosis, and/or treatment of endometriosis. Patent Application Publication Sep. 1, 2016 Sheet 1 of 3 US 2016/025 1718A1 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Pathology? Classifier Disease Other (Non-Endo) Severity? Severity MOd -Severe Classifier FIG. 1 Patent Application Publication Sep. 1, 2016 Sheet 2 of 3 US 2016/025 1718A1 COnStruction Construct classifier with these samples. Validation Walidate Classifier with these Samples. FIG. 2 Train Train Classifier with these Samples. Construction Test Test Classifier with these Samples. FIG. 3 Patent Application Publication Sep. 1, 2016 Sheet 3 of 3 US 2016/025 1718A1 I/O SYSTEM CENTRAL PRINTER CONTROLLER MEMORY PROCESSOR 871 872 873 874 DISPLAY STORAGE EXTERNAL SERIALPORT KEYBOARD ADAPTER 877 878 DEVICE(S) INTERFACE 882 879 881 MONITOR 876 \- 800 FIG. 4 US 2016/025 1718A1 Sep. 1, 2016 ENDOMETROSS CLASSIFIER ity of endometriosis in a Subject. In one aspect, a method for diagnosing endometriosis is described, the method compris CROSS-REFERENCES TO RELATED 1ng: APPLICATIONS 0007 determining the expression level of at least one set of genes, the set of genes comprising the genes in 0001. The present application claims priority from and the Table 7, Table 8, Table 9, Table 10, Table 11, Table 12, benefit of U.S. Provisional Application No. 61/885,284, filed Table 13, Table 14, or Table 15, in a tissue sample com Oct. 1, 2013, titled “ENDOMETRIOSIS CLASSIFIER, the prising endometrial cells from a subject; entire contents of which are incorporated herein by reference 0008 associating the expression level with the presence for all purposes. and severity of endometriosis; and 0009 providing a diagnosis of the presence, absence or STATEMENT AS TO RIGHTS TO INVENTIONS severity of endometriosis based on the association. MADE UNDER FEDERALLY SPONSORED 0010. In some embodiments, the method can be a com RESEARCH AND DEVELOPMENT puter implemented method. For example, in one embodi 0002 This invention was made with government support ment, a computer implemented method is provided, the under grant NIH/NICHD U54HD055764 awarded by the method comprising: National Institutes of Health Eunice Kennedy Shriven 0.011 (i) receiving the expression data of at least one set National Institute of Child Health and Human Development. of genes, the set of genes comprising the genes in Table The government has certain rights in this invention. 7, Table 8, Table 9, Table 10, Table 11, Table 12, Table 13, Table 14, and/or Table 15; and 0012 (ii) associating the expression data of the at least REFERENCE TO A “SEQUENCE LISTING. A one set of genes with the presence, absence or severity of TABLE, ORACOMPUTER PROGRAM LISTING endometriosis, thereby diagnosing endometriosis. APPENDIX SUBMITTED AS ANASCII TEXT 0013. In another aspect, a method for detecting the expres FILE sion of genes in a tissue sample comprising endometrial cells 0003 Tables 16, 17, and 18, created on Sep. 23, 2013, or tissue is described, the method comprising: machine format IBM-PC, MS-Windows operating system, 0.014 detecting the expression level of at least one set of submitted herewith on six (6) compact discs (CD-R) accord genes, the set of genes comprising the genes in Table 7. ing to 37 C.F.R. 1.52(e)(1) and 1.77(b)(5), are hereby incor Table 8, Table 9, Table 10, Table 11, Table 12, Table 13, porated by reference in their entirety for all purposes. Com Table 14, or Table 15, in a tissue sample comprising pact disc 1 contains Table 16, copy 1, 6,010,697 bytes. endometrial cells from a subject. Compact disc 2 contains Table 16, copy 2, 6,010,697 bytes. 0015. In some embodiments of the above aspects, the Compact disc 3 contains Table 17, copy 1, 6,051,004 bytes. methods comprise determining or detecting expression of the Compact disc 4 contains Table 17, copy 2, 6,051,004 bytes. at least one set of genes by hybridizing RNA isolated from the Compact disc 5 contains Table 18, copy 1, 6,066.294 bytes. endometrial tissue sample to a microarray. In some embodi Compact disc 6 contains Table 18, copy 2, 6,066.294 bytes. ments, the methods comprise determining or detecting expression of the at least one set of genes by amplifying RNA BACKGROUND OF THE INVENTION from the tissue samples using PCR. In some embodiments, the methods comprise determining or detecting expression of 0004 Endometriosis is a complex disorder associated the at least one set of genes by determining or measuring the with pelvic pain and infertility, and is characterized by the expression level of proteins encoded by the at least one set of implantation of endometrial tissue outside the uterus, prima genes. rily on the pelvic peritoneum and ovaries (Giudice L. C. Kao 0016. In some embodiments, the method further com L C (2004) The Lancet 364:1789-99). Endometriosis affects prises obtaining a sample comprising endometrial cells or 6-10% of women in the general population and 35-50% of tissue. The sample comprising endometrial cells or tissue can women with pain and/or infertility (Eskenazi B. Warner ML be obtained directly from a subject or patient, such as by (1997) Obstet Gynecol Clin North Am 24:23.5-58). It is Surgery or biopsy, or can be obtained indirectly from a health widely accepted that by retrograde menstruation (Sampson J care provider, such as a doctor, who performed the Surgery or A (1927) Am J ObstetGynecol 14:442-469), endometrial biopsy procedure. In one embodiment, the method comprises tissue establishes itself on the peritoneum of women with identifying a Subject in need of treatment for endometriosis or endometriosis due to heritable and/or acquired defects that another uterine pathology. confer Survival advantage and promote attachment, growth, 0017. In another aspect, kits that are useful for diagnosing neoangiogenesis, and invasion into the peritoneum. endometriosis are provided. For instance, in Some embodi 0005. The main clinical symptoms of endometriosis are ments, the kit comprises a plurality of oligonucleotides that pelvic pain, bleeding and infertility, with the latter proposed specifically hybridize to mRNA, or a complement thereof, to be related to impaired implantation due, in part, to impaired expressed by a set of genes, the set of genes comprising the decidualization of endometrial stromal fibroblasts (ESFs). genes in Table 7, Table 8, Table 9, Table 10, Table 11, Table This application provides methods and compositions that are 12, Table 13, Table 14, or Table 15, or any combination useful for diagnosing endometriosis. thereof. In some embodiments, the kit comprises a set of oligonucleotides that specifically hybridize to mRNA, or a BRIEF SUMMARY OF THE INVENTION complement thereof, expressed by the set of genes in Table 7. the set of genes in Table 8, the set of genes in Table 10, the set 0006. The present application provides methods and com of genes in Table 11, the set of genes in Table 13, or the set of positions for diagnosing the presence, absence and/or sever genes in Table 14. In one embodiment, the kit comprises a set US 2016/025 1718A1 Sep. 1, 2016 of oligonucleotides that specifically hybridize to mRNA, or a endometriosis. The use can also provide a prognosis regard complement thereof, expressed by the set of genes in Table 9 ing the course of disease, or can be used to identify a subject the set of genes in Table 12, or the set of genes in Table 15. In as a candidate for treatment for endometriosis. In some Some embodiments, the kit comprises a set of probes for embodiments, the composition is for use in a method for detecting nucleic acids or proteins expressed by a plurality of treating endometriosis, wherein the treatment regimen is the genes in Tables 7-15. determined or modified based on the expression levels of at 0018. In some embodiments, the kit comprises reagents least one of the sets of genes in Table 7, Table 8, Table 9, Table that detect the expression of a protein encoded by or 10, Table 11, Table 12, Table 13, Table 14, or Table 15, in a expressed by a plurality of the genes in Table 7, Table 8, Table tissue sample comprising endometrial cells from a Subject. 9, Table 10, Table 11, Table 12, Table 13, Table 14, or Table 0029. Further embodiments of the invention are described 15. In some embodiments, the reagent is an antibody or herein.
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