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(12) United States Patent (10) Patent No.: US 8,637.240 B2 Tian Et Al

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(12) United States Patent (10) Patent No.: US 8,637.240 B2 Tian Et Al USOO8637240B2 (12) United States Patent (10) Patent No.: US 8,637.240 B2 Tian et al. (45) Date of Patent: Jan. 28, 2014 (54) USE OF GENE EXPRESSION SIGNATURES FOREIGN PATENT DOCUMENTS TO DETERMINE CANCERGRADE WO WO-2006,131599 12/2006 (75) Inventors: Qiang Tian, Seattle, WA (US); Greg D. OTHER PUBLICATIONS Foltz, Seattle, WA (US); Leroy Hood, Seattle, WA (US); Xiaowei Yan, Pusztai et al., Clinical trial design for microarray predictive marker Bellevue, WA (US) discovery and assessment, Annals of Oncology 15: 1731-1737. 2004. (73) Assignee: Institute for Systems Biology, Seattle, Kroese et al., Genetic tests and their evaluation: Can we answer the WA (US) key questions?, Genet Med 2004:6(6);475-480.* Golubet al., Molecular Classification ofCancer: Class Discovery and (*) Notice: Subject to any disclaimer, the term of this Class Prediction by Gene Expression Monitoring, Science vol. 286 patent is extended or adjusted under 35 Oct. 15, 1999.* U.S.C. 154(b) by 0 days. Toren et al., CD133-Positive Hematopoietic StemCell “Sternness” Genes Contain Many Genes Mutated or Abnormally Expressed in (21) Appl. No.: 12/892,710 Leukemia, Stem Cells 2005:23:1142-1153.* Wright et al., Brcal breast tumors contain distinct CD44+CD24 (22) Filed: Sep. 28, 2010 and CD133+ cells with cancer stem cell characteristics, Breast Can cer Research 2008, 10:R10.* (65) Prior Publication Data Beier, CD133+and CD133- Glioblastoma-Derived Cancer Stem Cells Show Differential Growth Characteristics and Molecular Pro US 2011 FO1 O5340 A1 May 5, 2011 files, Cancer Res 2007; 67: (9). May 1, 2007, 4010-15.* Beier et al., Cancer Research (2007) 67(9):40 10-4015. Related U.S. Application Data International Search Report and Written Opinion for PCT/US 10/ 50564, mailed Dec. 16, 2010, 5 pages. (60) Provisional application No. 61/277,723, filed on Sep. Ben-Porathet al., Nat. Genet. (2008) 40:499-507. 28, 2009. Liu et al., New England Journal of Medicine (2007) 356:217-226. Setlur et al., Cancer Research (2007) 67: 10296-103.03. (51) Int. C. CI2O I/68 (2006.01) * cited by examiner GOIN33/574 (2006.01) (52) U.S. C. Primary Examiner — Jim Ketter USPC ........................................... 435/6.1; 435/723 Assistant Examiner — Reza Ghafoorian (58) Field of Classification Search (74) Attorney, Agent, or Firm — Morrison & Foerster LLP None See application file for complete search history. (57) ABSTRACT Signatures indicative of cancer grades are based on over- and (56) References Cited under-expression of 214 genes that characterize expression U.S. PATENT DOCUMENTS patterns in CD133" cells. 2009. O157326 A1 6, 2009 Dai et al. 5 Claims, 7 Drawing Sheets CD 133 Neg CD133-up (89 genes) up r red down = green CD 133-down (125 genes) - -- y w U.S. Patent Jan. 28, 2014 Sheet 1 of 7 US 8,637,240 B2 CD133 Neg CD133-up i (89 genes) up red down = green CD 133-down (125 genes) . - O - - Figure 1 U.S. Patent Jan. 28, 2014 Sheet 2 of 7 US 8,637,240 B2 D133P Owl Figure 2 U.S. Patent Jan. 28, 2014 Sheet 4 of 7 US 8,637,240 B2 4a C33 33N {BE-tor C2 OS AC3. (33 3. 4b cp133P I. Its 33N tink Figure 4 Figure 5 U.S. Patent Jan. 28, 2014 Sheet 5 Of 7 US 8,637,240 B2 i U.S. Patent Jan. 28, 2014 Sheet 6 of 7 US 8,637,240 B2 . : a as e & 8 x 8. U.S. Patent Jan. 28, 2014 Sheet 7 Of 7 US 8,637,240 B2 8a 33 (33.3N {race Grade 2 rade 3 C133P 133N Figure 8 US 8,637,240 B2 1. 2 USE OF GENE EXPRESSION SIGNATURES under-expression for each group of said 10 genes in CD133" TO DETERMINE CANCER GRADE vs. CD133 cells, whereby the degree of correlation between the collective expression levels in the tumor tissue and the CROSS-REFERENCE TO RELATED collective levels in the same genes of Table 1 in CD133 vs. APPLICATIONS CD133 cells indicates the grade of said tumor. More precise results may be obtained by increasing the This application claims priority from U.S. provisional number of genes that are included in the “up' and “down” application 61/277,723 filed 28 Sep. 2009. The contents of panels to be assessed. A correlation of the expression pattern this document are incorporated herein by reference. found in the tumor sample with the expression pattern found 10 in CD133 cells is indicative of a more aggressive cancer. STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED BRIEF DESCRIPTION OF THE DRAWINGS RESEARCH FIG. 1 shows the expression patterns of the CD133-up (89 This work was Supported in part by grants from the 15 genes) and CD133-down (125 genes) signatures in CD133" National Institutes of Health, grant numbers P01 DK53074, vs. CD133 cell populations isolated from five glioblastoma CA 119347 and P50 GM 076547. The U.S. government has (GBM) patients. Each line in the heat map represents a P value for overexpression (red) or underexpression (green) of certain rights in this invention. the given signature calculated from 10 computational itera TECHNICAL FIELD tions. FIG. 2 shows the heat map of P values for expression The invention relates to gene expression patterns in various patterns of the 89 up/125 down signatures in seven replicate tumor tissues. Specifically, statistical methods are employed stem cell cultures as related to the patterns in CD133 cells. to compare signature levels of genes over- or under-expressed FIG.3 shows the clustering of gene expression profiles of in CD133 cells with tissue samples from subjects. Tumors 25 primary GBM samples either cultured in serum-containing that exhibit patterns characteristic of CD133 cells are diag medium which encourages differentiation or stem cell enrich nostic of more aggressive tumors. ing medium, which maintains undifferentiated status. FIGS. 4a–b show signatures as compared to the expected BACKGROUND ART up/down profiles in tissue samples isolated from patients with 30 various grades of glioma. FIG. 4a is a heat map of P value, Cancer stem cells (CSC) are believed to be responsible for wherein each vertical line represents a patient sample aggressive tumor growth. CSC have been reported to be char grouped according to histopathological stages, labeled as acterized by the presence of the transmembrane protein non-tumor (control), AC2 (grade 2 astrocytoma), ODG2 CD133, although contradictory studies indicating that there (grade 2 oligodendroglioma), AC3 (grade 3 astrocytoma), may not be a one-to-one correlation between CD133 cells 35 ODG3 (grade 3 oligodendroglioma), and GBM (grade 4 and aggressive tumor growth have also appeared. It has been astrocytoma). FIG. 4b shows the P values of over- or under shown clinically for breast cancer that determining the pres expression for each subgroup of patients calculated according ence of CSC is useful in prognosis of outcome (Liu, R., et al., to the hypergeometric distribution. New Engl. J. Med. (2007) 356:217-226). Additional correla FIG. 5 shows the enrichment pattern of the CD133 gene tions have been found in glioblastoma multiforme (GBM) the 40 signatures in different GBM molecular subtypes: Proneural, most deadly form of brain cancer (Ben-Porath, I., et al., Nat. Classical, Mesenchymal, and Neural. Probabilistic values for Genet. (2008)40:499-507). gene-set enrichment are used to draw the heat map: red, All documents and citations listed herein are incorporated enrichment for overexpression with probabilistic values herein by reference in their entirety. toward 0; green, enrichment for underexpression with proba Because correlation of CD133" markers with tumor 45 bilistic values toward 1; black, no significant change, proba aggressiveness has not been demonstrated, alternative profil bilistic values toward 0.5. ing methods have been designed. Various signatures have FIGS. 6a, 6b and 6c show survival curves of CD133 active been proposed by, for example. OncoMed. The present inven vs CD133 inactive/others in three independent GBM tion provides profiles that are more successful in assessing datasets. prognosis. 50 FIG. 7 shows distribution of genomic mutations among three CD133 classes of GBM patients. Mutation and gene DISCLOSURE OF THE INVENTION expression data were obtained from published TCGA datasets. The invention is directed to expression profiles character FIGS. 8a-b show results similar to those in FIGS. 4a–b in istic of various stages or grades of tumor development. The 55 samples from individuals with different grades of breast can present inventors have identified 89 genes whose expression C. is significantly elevated and 125 genes whose expression is significantly decreased in CD133 cells. As it has been deter MODES OF CARRYING OUT THE INVENTION mined herein that this signature correlates with the corre sponding signature associated with stem cells, and relevance 60 The invention relies on Statistical treatment of expression of the signature to cancer grade has been established. patterns obtained using standard microarray technology. Thus, in one aspect, the invention is directed to a method to Expression patterns are compared to profiles associated with assess the grade of a tumor in a Subject, which method com CD133 cells collectively using an unbiased algorithm devel prises assessing the collective level of expression of at least oped by Setlur, S. R., et al., Cancer Res. (2007) 67:10296 10 genes in each of the overexpressed and/or underexpressed 65 103.03. In this analysis, the entire profile of a given subset of groups set forth in Table 1 and comparing the resulting col genes (e.g., the CD133-up, or the CD133-down) is compared lective levels with the collective levels with respect to over- or to the entire profile of the same set of genes in CD133 US 8,637,240 B2 3 4 expression to denote collective under- and over-expression.
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