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(12) United States Patent (10) Patent No.: US 9,371,569 B2 Van Criekinge Et Al

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(12) United States Patent (10) Patent No.: US 9,371,569 B2 Van Criekinge Et Al US009371569B2 (12) United States Patent (10) Patent No.: US 9,371,569 B2 Van Criekinge et al. (45) Date of Patent: Jun. 21, 2016 (54) DETECTION AND PROGNOSIS OF (52) U.S. Cl. CERVICAL CANCER CPC ........ CI2O I/6886 (2013.01); C12O 2600/1 12 (2013.01); C12O 2600/154 (2013.01); C12O (71) Applicant: MDxHealth SA, Sart-Tilman (BE) 2600/16 (2013.01) (58) Field of Classification Search (72) Inventors: Wim Van Criekinge, Sart-Tilman (BE); None Valerie Deregowski, Sart-Tilman (BE). See application file for complete search history. Luc Dehaspe, Sart-Tilman (BE); G. Bea A. Wisman, Groningen (NL); Ate G. J. (56) References Cited Van der Zee, Groningen (NL); E. M. D. Schuuring, Groningen (NL) U.S. PATENT DOCUMENTS 2005/0250137 A1* 1 1/2005 Tainsky et al. .................... 435/6 (73) Assignee: MDxHealth S.A., Herstal (BE) 2010/0.14483.6 A1* 6/2010 Van Engeland et al. ... 514/44 A (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. WO WO 2006113678 A2 * 10, 2006 OTHER PUBLICATIONS (21) Appl. No.: 14/180,239 Widschwendter et al., Gynecologic Oncology, 2004 vol. 93 pp. 407 (22) Filed: Feb. 13, 2014 416. (65) Prior Publication Data * cited by examiner US 2015/OO17634 A1 Jan. 15, 2015 Primary Examiner — Michele KJoike Assistant Examiner — Mindy G Brown Related U.S. ApplicationO O Data Property(74) Attorney, Law, LLPAgent, or Firm — Andrus Intellectual (63) applicationContinuation No. of applicationPCT/EP2009/053386 No. 12/933,747, on Mar. filed 23, as (7) ABSTRACT 2009, now abandoned. The present invention relates to methods and kits for identi fying, diagnosing, prognosing, and monitoring cervical can (60) Eyal application No. 61/038,549, filed on Mar. cer. These methods include determining the methylation sta s tus or the expression levels of particular genes, or a (51) Int. Cl combination thereof. (2006.01) 23 Claims, 15 Drawing Sheets U.S. Patent Jun. 21, 2016 Sheet 1 of 15 US 9,371,569 B2 Figure 1A U.S. Patent Jun. 21, 2016 Sheet 2 of 15 US 9,371,569 B2 Figure 1B U.S. Patent Jun. 21, 2016 Sheet 3 of 15 US 9,371,569 B2 Figure 1C U.S. Patent Jun. 21, 2016 Sheet 4 of 15 US 9,371,569 B2 Figure 2 t cy 40 2 a. s S a 30 2 .9s 2O > 2d C 10 s Z, O O 1 OOOO 2OOOO 3OOOO 4OOOO 5OOOO 6OOOO Number of selected probes U.S. Patent Jun. 21, 2016 Sheet 5 Of 15 US 9,371,569 B2 U.S. Patent Jun. 21, 2016 Sheet 6 of 15 US 9,371,569 B2 U.S. Patent US 9,371,569 B2 53,5g.I U.S. Patent Jun. 21, 2016 Sheet 9 Of 15 US 9,371,569 B2 Figure 6A .. EPE's 31st O. Sas Sox 253 SLT2 .367. PA 33 3. X IER3. : fi. Oxas 23844 Oct 387: s ... A 353 x4, 25.2 C3orf5885 .. surr iss 3. 3 COH4.435. KK 23: start gris ALX325iSAssist OKKK 2397323:373 RECKS34RECK 18340 ISI 32. seriesserfs as Sox iss CYCLE SSsist 2388238 is FK coA123253C.A. 1325. pax grid this U.S. Patent Jun. 21, 2016 Sheet 11 of 15 US 9,371,569 B2 Figure 7 Act it Amplification Plot s s Cycle Detector Tac156137 parn vs. cycle threshadoogaagi U.S. Patent Jun. 21, 2016 Sheet 12 of 15 US 9,371,569 B2 Figure 8 Alicatirict 1.008 E-1 uae 3 30 E4 - s Cycle 333. etc. Tac s & PictIarn ws. Cycle & Threshold: U.S. Patent Jun. 21, 2016 Sheet 13 of 15 US 9,371,569 B2 Figure 9 TAC156187 (99.35% efficiency) 40 35 30 Ct 25 15 10 O 1 2 3 4. 5 6 7 Log Copies y = -3.3374x + 39.493 R2 = 0.9995 U.S. Patent Jun. 21, 2016 Sheet 14 of 15 US 9,371,569 B2 Figure 10 Walid MSP assay Copy number Copy number Copy number ACTE & 10 ACTE. 1)-OO ACTE - OO Copy number Copy number Test gene < 1 Test gene < 1 Ratio = 1000 X (Copy number Test gene Copy number ACTB) Test gene dependent Test gene dependent Ratio < cut off Rati Cut Off U.S. Patent Jun. 21, 2016 Sheet 15 Of 15 US 9,371,569 B2 e 2 y A. i US 9,371,569 B2 1. 2 DETECTION AND PROGNOSS OF absolute and its longevity is uncertain; as yet, the possibility CERVICAL CANCER of genotype replacement cannot be excluded; and older women not covered by vaccination programs will continue to FIELD OF THE INVENTION be at risk. Therefore, cervical screening will still be required for control. The present invention relates to the area of cancer diagnos Cancer biomarkers have been described in literature and tics and therapeutics. In particular, it relates to methods and aberrant methylation of genes has been linked to cervical kits for identifying, diagnosing, prognosing, and monitoring cancer (Virmani et al., 2001). In addition, methylation mark cervical cancer. These methods include determining the ers may serve for predictive purposes as they often reflect the methylation status or the expression levels of particular 10 sensitivity to therapy or duration of patient Survival. genes, or a combination thereof. DNA methylation is a chemical modification of DNA per formed by enzymes called methyltransferases, in which a BACKGROUND TO THE INVENTION methyl group (m) is added to certain cytosines (C) of DNA. Cervical cancer is the fifth most deadly cancer in women. 15 This non-mutational (epigenetic) process (mC) is a critical Worldwide, approximately 500,000 cases of cervical cancer factor in gene expression regulation. (See J. G. Herman, are diagnosed and about 250,000 women die from this disease Seminars in Cancer Biology, 9: 359-67, 1999). annually (www.who.int/mediacentre/factsheets). An early diagnosis is critical for the Successful treatment of Most (80-90%) invasive cervical cancer develops in flat, many types of cancer, including cervical cancer. If the exact scaly Surface cells that line the cervix (called squamous cell methylation profiles of cervical tumors are available and carcinomas, SCC). Approximately 10-15% of cases develop drugs targeting the specific genes are obtainable, then the in glandular Surface cells (called adenocarcinomas, AdC). treatment of cervical cancer could be more focused and ratio Less commonly, cervical cancers have features of both SCC nal. Therefore, the detection and mapping of novel methyla and AdC. These are called adenosquamous carcinomas or tion markers is an essential step towards improvement of mixed carcinomas (www.cancer.org). 25 cervical cancer prevention, Screening, and treatment. Thus, During the process of cervical cancer development, normal there is a continuing need in the art to identify methylation cervical cells gradually develop pre-cancerous changes that markers that can be used for improved assessment of cervical turn into cancer. Cervical cancer evolves from pre-existing CaCC. noninvasive premalignant lesions referred to as cervical intraepithelial neoplasias (CINs), ranging from CINI (mild 30 SUMMARY OF THE INVENTION dysplasia) to CIN II (moderate dysplasia) to CIN III (severe dysplasia/carcinoma in situ). This process usually takes sev The present invention is based on the finding that several eral years but sometimes can happen in less than a year. For genes are identified as being differentially methylated in cer most women, pre-cancerous cells will remain unchanged and Vical cancers. This information is useful for cervical cancer disappear without any treatment. 35 screening, risk-assessment, prognosis, disease identification, Screening for malignant and premalignant disorders of the disease staging, and identification of therapeutic targets. The cervix is usually performed according to the Papanicolaou identification of new genes that are methylated in cervical (PAP) system. The cervical smears are examined by light cancer allows accurate and effective early diagnostic assays, microscopy and the specimens containing morphologically methylation profiling using multiple genes and identification abnormal cells are classified into PAP I to V, at a scale of 40 of new targets for therapeutic intervention. increasing severity of the lesion. But, present PAP test has Accordingly, in a first aspect, the invention provides a Some limitations and is not completely ideal for screening as method for identifying cervical cancer or its precursor, or it suffers from suboptimal single-test sensitivity, limited predisposition to cervical cancer. Epigenetic modification of reproducibility, and many equivocal. at least one gene selected from the group consisting of genes There is a strong association between certain Subtypes of 45 according to Table 1, is detected in a test sample containing the Human Papillomavirus (HPV) and cervical cancer. Stud cervical cells or nucleic acids from cervical cells. The test ies have shown that only high-risk HPV types are involved in sample is identified as containing cells that are neoplastic, the progression from cytological normal cervix cells to high precursor to neoplastic, or predisposed to neoplasia, or as grade squamous intraepithelial lesions. Around 15 high-risk containing nucleic acids from cells that are neoplastic, pre (cancer-causing) HPV types have been identified. Although it 50 cursor to neoplastic, or predisposed to neoplasia. has been Suggested that high-risk HPV testing may improve Preferably, the at least one gene is selected from a group of cervical cancer Screening, the specificity for high grade cer genes consisting of JAM3. LMX1A, CDO1, NID2, ALX3, vical neoplasia of high risk HPV testing is relatively low. This ALX4, AR, ARID4A, ATM, AURKA, B4GALT1, BMP2, low specificity of HPV testing leads to a higher number of BMP6, BNIP3, C13orf18, C16orf248, C90rf19, CALCA, unnecessarily follow-up diagnostic workups (e.g.
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