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(12) United States Patent (10) Patent No.: US 8,067,168 B2 Ordway Et Al

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(12) United States Patent (10) Patent No.: US 8,067,168 B2 Ordway Et Al USOO80671 68B2 (12) United States Patent (10) Patent No.: US 8,067,168 B2 Ordway et al. (45) Date of Patent: Nov. 29, 2011 (54) GENE METHYLATION IN CANCER OTHER PUBLICATIONS DAGNOSIS GenBank Locus AF369786 Homo sapiens growth hormone Secretagogue receptor gene, complete cols, alternatively spliced (Jul. (75) Inventors: Jared Ordway, St. Louis, MO (US); 7, 2001), from www.ncbi.nlm.nih.gov. 5 printed pages.* Jeffrey A. Jeddeloh, Oakville, MO Juppner H. Bone (1995) vol. 17 No. 2 Supplement, pp. 39S-42S.* (US); Joseph Bedell, Chesterfield, MO GenBank Locus AC069523 “Homo sapiens 3 BAC RP11-1K20 (Roswell Park Cancer Institute Human BAC Library) complete (US) sequence” (Aug. 30, 2002) from www.ncbi.nlm.nih.gov, pp. 1-31.* Rein T. et al. Nucleic Acids Research (1998) vol. 26, No. 10, pp. (73) Assignee: Orion Genomics LLC, St. Louis,MO 2255-2264. (US) Gaytan F. etal. The Journal of Clinical Endocrinology & Metabolism (Mar. 2005) vol. 90, No. 3, pp. 1798-1804.* (*) Notice: Subject to any disclaimer, the term of this Cmaeron E.E. et al Blood (Oct. 1, 1999) vol. 94, No. 7, p. 2445 patent is extended or adjusted under 35 2451.* Costello, Josoph F. et al.; “Graded Methylation in the Promoter and U.S.C. 154(b) by 462 days. BOdy of the O-Methylguanine DNA Methyltransferase (MGMT) Gene Correlates with MGMT Expression in Human Glioma Cells'; (21) Appl. No.: 11/809,355 1994. The Journal of Biological Chemistry, vol. 269, No. 25, pp. 17228-17237. (22) Filed: May 30, 2007 Widschwendter, Martin et al.; "Methylation and Silencing of the Retinoic Acid Receptor-B2 Gene in Breast Cancer'; 2000, Journal of (65) Prior Publication Data the National Cancer Institute, vol. 92, No. 10, pp. 826-832. Bae, Young Kyung et al., “Hypermethylation in histologically dis US 2007/O2985O6A1 Dec. 27, 2007 tinct classes of breast cancer'; 2004, Clinical Cancer Research. An Official Journal of the American Association for Cancer Research, Related U.S. Application Data vol. 10, No. 18, pp. 5998-6005. Makiyama, K. et al.; "Aberrant expression of HOX genes in human (60) Provisional application No. 60/803,571, filed on May invasive breast carcinoma'; 2005. Oncology Reports, vol. 13, No. 4. 31, 2006, provisional application No. 60/848,543, pp. 673-679. filed on Sep. 28, 2006. Yan, P.S. et al.; “Differential distribution of DNA methylation within the RASSF1A CpG island in breast cancer’: 2003, Cancer Research, (51) Int. Cl. vol. 63, No. 19, pp. 6178-6186. CI2O I/68 (2006.01) CI2P 19/34 (2006.01) * cited by examiner C7H 2L/02 (2006.01) Primary Examiner — Stephen Kapushoc (52) U.S. Cl. ........................ 435/6.1; 435/91.2:536/23.1 (74) Attorney, Agent, or Firm — Kilpatrick Townsend & (58) Field of Classification Search ........................ None Stockon LLP See application file for complete search history. (57) ABSTRACT (56) References Cited The present invention provides DNA biomarker sequences U.S. PATENT DOCUMENTS that are differentially methylated in samples from normal individuals and individuals with cancer. The invention further 2004/023496.0 A1* 11/2004 Olek et al. ........................ 435/6 provides methods of identifying differentially methylated FOREIGN PATENT DOCUMENTS DNA biomarker sequences and their use in detecting and WO WO O2/OO927 A2 1, 2002 diagnosing cancer. WO WO O2, 18632 A2 3, 2002 WO WO 2007/O16668 A2 2, 2007 14 Claims, 18 Drawing Sheets U.S. Patent Nov. 29, 2011 Sheet 1 of 18 US 8,067,168 B2 U.S. Patent Nov. 29, 2011 Sheet 3 of 18 US 8,067,168 B2 ??????). 3æðxxxxxxxx 3 ??38 * *****?g U.S. Patent Nov. 29, 2011 Sheet 4 of 18 US 8,067,168 B2 ¿??????? 3 &#33xxxx ..?$$.3 33 3 * * U.S. Patent Nov. 29, 2011 Sheet 5 of 18 US 8,067,168 B2 U.S. Patent Nov. 29, 2011 Sheet 6 of 18 US 8,067,168 B2 U.S. Patent US 8,067,168 B2 *********3 3.***33 ?au??a & 33.ag }} { 3 $$$$ {{}} U.S. Patent Nov. 29, 2011 Sheet 8 of 18 US 8,067,168 B2 Figure 6. Demonstration of threshold adjustment for determining sensitivity and specificity. ha1p 39189; Locus number 2 Tumor Normal Blood n = 25 in a 25 n 24 U.S. Patent US 8,067,168 B2 O U.S. Patent Nov. 29, 2011 Sheet 10 of 18 US 8,067,168 B2 Figure 8. Correlation between qPCR based DNA methylation detection and 5 methylcytosine content measured by bisulfite sequencing. SO ... - -o-o: ------na-a-War-wa-a- y = 0.1838x +0.0391 Rs 0.7965 ( 50% f R i.40% -1 O. 30% . -1 : 20% - 2 a 10% e 0. 0. O% O 0.5 15 2 2.5 MethylScreen Avg. dCt N-- N-- Normat Tutor U.S. Patent Nov. 29, 2011 Sheet 12 of 18 US 8,067,168 B2 Figure 10A. Detection of tumor-specific DNA methylation in Stage I breast tumors relative to Stage II-III breast tumors. 3 - y = 0.9815x w w m IM y = X 8 s S O 20 40 60 80 100 Frequency (Stage I/III) U.S. Patent Nov. 29, 2011 Sheet 14 of 18 US 8,067,168 B2 Figure 11A. Examples of DNA methylation data for four selected biomarker loci. Biomarker Locus Number: 2 wa c o s C c r C -i: -- i. Blood Normal Tumor Blood Normal Tumor Biomarker Locus Number: f se s Blood Normal Tumor Blood Normal Tumor U.S. Patent Nov. 29, 2011 Sheet 15 of 18 US 8,067,168 B2 Figure 11B. ROC curve plots for loci shown in Figure 11A. OO 0.2 O4 O6 O8 O 1-Specificity U.S. Patent Nov. 29, 2011 Sheet 16 of 18 US 8,067,168 B2 Figure 12. Analysis of DNA methylation by bisulfite sequencing. A. B. ao. 80% Ros 2. 60% g 60% E 40% & 40% E g is no < 20% g 20% a. 0% 0% r O 2 3 4 5 2 3 4. 5 C. Avg delta Ct D. CpG position 100% O 100% 80% 3. 80% s hur E 60% 60% SS O) 40% E 40% 3. SS 20% ------ 0% CC O upour full- T T - 4 1 2 3 4 5 6 7 8 9 CpG position E. F. 100% () 3. 80% has 3. 60% C E 40% SS 20% O% 0% O 2 3 4. 1 2 3 4 5 6 7 Avg delta Ct CpG position t 80% 80% () D 60% s 60% s E t SS 40% 2 40% g SS C 20% g 20% 0% 3 || -- *-tt-, i.e., O 1 2 3 4. 1 2 3 4 5 6 7 8 9 Avg delta Ct CpG position U.S. Patent Nov. 29, 2011 Sheet 17 of 18 US 8,067,168 B2 Figure 13. Hypermethylation is associated with decreased transcription. Tumor 2 Tumor 3 g wa s v s sa) s s s s we U.S. Patent Nov. 29, 2011 Sheet 18 of 18 US 8,067,168 B2 Figure 14, DNA methylation detection in fine needle aspirate specimens. 100% y = 0.817x + 0.0038 90% R = 0.7417 80% 70% 60% 50% 40% 40% 50%. 60% 70% 80% 90%. 100% % POSITIVE TUMOR US 8,067,168 B2 1. 2 GENE METHYLATION IN CANCER targeting these early changes, leading to more effective can DAGNOSIS cer treatment. The present invention addresses these and other problems. CROSS-REFERENCE TO RELATED PATENT APPLICATIONS BRIEF SUMMARY OF THE INVENTION The present application claims benefit of priority to U.S. The present invention provides methods for determining Provisional Patent application No. 60/803,571, filed May 31, the methylation status of an individual. In one aspect, the 2006, and U.S. Provisional Patent application No. 60/848, methods comprise: 543, filed Sep. 28, 2006, each of which are incorporated by 10 obtaining a biological sample from an individual; and reference in their entirety. determining the methylation status of at least one cytosine within a DNA region in a sample from the individual BACKGROUND OF THE INVENTION where the DNA region is a SEQID NO: selected from the group consisting of 213, 214, 215, 216, 217, 218, Human cancer cells typically contain Somatically altered 15 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, genomes, characterized by mutation, amplification, or dele 230, 231, 232, 233,234, 235, 236, 237, 238,239, 240, tion of critical genes. In addition, the DNA template from 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, human cancer cells often displays Somatic changes in DNA 252,253,254, 255, 256, 257, 258, 259, 260, 261,262, methylation. See, e.g., E. R. Fearon, etal, Cell 61:759 (1990); 263,264, and 265. P. A. Jones, et al., Cancer Res. 46:461 (1986); R. Holliday, In a further aspect, the methods comprise determining the Science 238:163 (1987); A. De Bustros, et al., Proc. Natl. presence or absence of cancer (including but not limited to Acad. Sci. USA 85:5693 (1988); P. A. Jones, et al., Adv. breast, lung, renal, liver, ovarian, head and neck, thyroid, Cancer Res. 54:1 (1990); S. B. Baylin, et al., Cancer Cells bladder, cervical, colon, endometrial, esophageal, or prostate 3:383 (1991); M. Makos, et al., Proc. Natl. AcadSci, USA cancer or melanoma) in an individual. 89:1929 (1992); N. Ohtani-Fujita, et al., Oncogene 8:1063 25 In some embodiments, the methods comprise: (1993). a) determining the methylation status of at least one DNA methylases transfer methyl groups from the universal cytosine within a DNA region in a sample from an indi methyl donor S-adenosyl methionine to specific sites on the vidual where the DNA region is at least 90%, 91%, 92%, DNA.
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