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US 2009/0270267 A1 Akiyama Et Al US 20090270267A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0270267 A1 Akiyama et al. (43) Pub. Date: Oct. 29, 2009 (54) COMPOSITION AND METHOD FOR (86). PCT No.: PCT/UP2006/309.177 DAGNOSINGESOPHAGEAL CANCER AND METASTASS OF ESOPHAGEAL CANCER S371 (c)(1), (2), (4) Date: Jan. 8, 2008 (75) Inventors: Hideo Akiyama, Kanagawa (JP); O O Satoko Kozono, Kanagawa (JP); (30) Foreign Application Priority Data 6A yet S. (JP): (JP): May 2, 2005 (JP) ................................. 2005-134530 Sam Nomura, Kanagaway): Sep. 13, 2005 (JP) ................................. 2005-265645 Hitoshi Nobumasa, Shiga (JP); Sep. 13, 2005 (JP) 2005-265678 Yoshinori Tanaka, Kanagawa (JP); O. l. 4UUC ) . Shiori Tomoda, Tokyo (JP); Publication Classification Yutaka Shimada, Kyoto (JP); Gozoh Tsujimoto, Kyoto (JP) (51) Int. Cl. C40B 30/04 (2006.01) Correspondence Address: CI2O I/68 (2006.01) BRCH STEWARTKOLASCH & BRCH GOIN 33/53 (2006.01) PO BOX 747 C40B 40/08 (2006.01) FALLS CHURCH, VA 22040-0747 (US) (52) U.S. Cl. ..................... 506/9; 435/6: 435/7.1:506/17 (73) Assignees: TORAY INDUSTRIES, INC., (57) ABSTRACT Tokyo (JP); Kyoto University, This invention relates to a composition, kit, or DNA chip Kyoto-shi (JP) comprising polynucleotides and antibodies as probes for detecting, determining, or predicting the presence or metasta (21) Appl. No.: 11/919,679 sis of esophageal cancer, and to a method for detecting, deter mining, or predicting the presence or metastasis of esoph (22) PCT Filed: May 2, 2006 ageal cancer using the same. Patent Application Publication Oct. 29, 2009 Sheet 1 of 5 US 2009/0270267 A1 Fig. 1 100% 80% 60% 40% 20% Number of genes for diagnosis Patent Application Publication Oct. 29, 2009 Sheet 2 of 5 US 2009/0270267 A1 Fig. 2 Patent Application Publication Oct. 29, 2009 Sheet 3 of 5 US 2009/0270267 A1 ig. 3 ? { H | | | | ! © | { { Patent Application Publication Oct. 29, 2009 Sheet 4 of 5 US 2009/0270267 A1 Fig. 4 10 15 20 Number of genes required for detecting esophageal cancer Patent Application Publication Oct. 29, 2009 Sheet 5 of 5 US 2009/0270267 A1 US 2009/0270267 A1 Oct. 29, 2009 COMPOSITION AND METHOD FOR which is found at the time of consultation following self DAGNOSING ESOPHAGEAL CANCER AND detection, has already progressed or metastasized outside the METASTASS OF ESOPHAGEAL CANCER esophageal wall, and Such a cancer often indicates a poor prognosis. Accordingly, lymph nodes around the esophagus FIELD OF THE INVENTION are often dissected at Surgery. If the presence or absence of metastasis can previously be expected, the area of the dissec 0001. The present invention relates to a composition for tion can be accurately determined prior to Surgery, or the area diagnosing (i.e., detecting, determining, or predicting) esoph of the dissection can be limited thereby contributing to the ageal cancer and metastasis of esophageal cancer, to a method patient's QOL after surgery. for detecting, determining, or predicting the presence or 0006 Esophageal cancer is definitely diagnosed by the metastasis of esophageal cancer using the composition, and to imaging test, endoscopy, and biopsy in the esophagus. Biopsy a kit for diagnosing the esophageal cancer or the metastasis of specimens are collected at the time of endoscopy or Surgery, the esophageal cancer using the composition. pathological specimens are prepared, and the diagnosis is made on the basis of the histopathological classification. BACKGROUND OF THE INVENTION Accordingly, there is a demand on development of a simple, 0002 The esophagus is a luminal organ that connects the rapid diagnosis technique that can predict the presence or pharynges and the stomach. The major parts thereof are absence of metastasis outside the esophagus based on the present in the thoracic cavity, and some parts are present in the properties of cells obtained by endoscopy. cervical region and in the abdominal cavity. In the upper 0007. Until now, the molecular-biological diagnosis tech portion of the thoracic cavity, the esophagus is located nique that involves the use of markers contained specifically between the trachea and the spine, and it is surrounded by the in esophageal cancer tissues has been proposed, which tech heart, the aorta, and the lungs in the lower portion. The nique can rapidly produce objective results and assist rapid esophagus delivers food ingested via the mouth to the stom diagnosis. ach. 0008. As the markers for clinical diagnosis of esophageal 0003. In 2001, the cancer mortality was 238.8 out of 100, cancer, serum protein markers, such as SCC, CYFRA21-1 000 patients in Japan. The percentages of total deaths and CEA, have been used so far. Besides them, proteins as accounted for by esophageal cancer have been increasing described in JP Patent Publication (kokai) No. 2003-259872 every year. In fiscal 2001, 5.0% of the male patients who died Aand JP Patent Publication (kohyo) No. 2000-511536A have of cancer died of esophageal cancer, and 1.4% of such female also been reported. However, these markers have poor sensi patients died of esophageal cancer. The peak ages for the tivity and specificity, and the sensitivity of CYFRA21-1, onset of esophageal cancer are in the 60s to 70s, and males are which is likely to have the highest sensitivity, is as low as more likely to develop esophageal cancer. Also, environmen about 33.9% (Nakamura, T. et al., 1998, Diseases of the tal factors such as Smoking, drinking, or preference for hot Esophagus, vol. 11, pp. 35-39) to about 43.9% (Kawaguchi, foods are closely related to the development of esophageal H. et al., 2000, Cancer, Vol. 89, pp. 1413-1417). Thus, this cancer. Further, it is known that blood vessels and lymph technique has not yet enabled to determine the presence or ducts are abundant in or around the esophageal wall and thus absence of esophageal cancer cells by detecting said serum a cancer developed in the esophagus often metastasizes. markers alone or in combination, nor is it possible to diagnose 0004 Methods for treating esophageal cancer are deter the metastasis of esophageal cancer using said markers. mined in accordance with the degree of progress (the Japan 0009. As another marker that utilizes genes for specifi Esophageal Society (ed.), Clinical Pathology: Rules for cally determining whether or not a biopsy sample from a Treating Esophageal Cancer, 1999), metastasis, and general Subject contains esophageal cancer cells, use of chromosome medical conditions. The standard method for treating esoph aberration (see, for example, JP Patent Publication (kokai) ageal cancer is described in "Guidelines for Treating Esoph No. 2001-17200 A and JP Patent Publication (kokai) No. ageal Cancer (the Japan Esophageal Society, 2002). At 2002-272497 A) and epigenetic sequences of genes (e.g., JP present, the most common treatment method is Surgery. The Patent Publication (kohyo) No. 2004-505612 A) has been esophagus, including the cancerous portion, and Surrounding disclosed. Also, a plurality of results of the exhaustive analy tissues, including lymph glands, are excised (i.e., lymph node sis of gene expression using a DNA chip have been reported dissection), and thereafter the esophagus is reconstructed (see, for example, Luo, A. et al., 2004. Oncogene, Vol. 23, pp. using other organs, such as Stomach. Surgery, particularly 1291-1299; Zhi, H. et al., 2003, International Journal of Can extensive regional lymph node dissection, imposes serious cer, vol. 106, pp. 327-333; Lu, J. et al., 2001, International burdens upon patients, and thus, lowered QOL after Surgery Journal of Cancer, Vol. 91, pp. 288-294; Kazemi-Noureini, S. should be an issue of concern. The early-stage cancer that et al., 2004, World Journal of Gastroenterology, Vol. 10, pp. remains in the mucosa may be occasionally treated by endo 1716-1721; Xu, S. H. et al., 2003, World Journal of Gastro scopic demucosation. Also, radiation therapy may be occa enterology, Vol. 9, pp. 417-422; and Su, H. et al., 2003, Cancer sionally carried out for both radical cures and symptomatic Research, Vol. 63, pp. 3872-3876). Furthermore, examples of therapy. Further, chemotherapy may be carried out in combi the reported markers that utilize a single gene expression as nation with Surgery or radiation therapy. At present, use of an indicator, include: SPRR3 gene (Small proline-rich pro 5-fluorouracil in combination with cisplatin is considered to tein 3) as described in WO 2003/042661, Chen, B. S. et al., be the most effective chemotherapy. 2000, Carcinogenesis, Vol. 21, pp. 2147-2150, Abraham, J. 0005 Esophageal cancer is often found by consultation M. et al., 1996, Cell Growth & Differentiation, vol. 7, pp. with a patient who has noticed symptoms, such as discomfort 855-860; fgf3 gene as described in Kitagawa, Y. et al., 1991, while Swallowing, Swallowing difficulty, retrosternal pain, or Cancer Research, Vol. 51, pp. 1504-1508; CSTB gene (cys chest discomfort. These symptoms, however, occur as a result tatin B, liver thiol proteinase inhibitor) as described in WO of the growth of cancer in the esophagus, and the cancer, 2003/042661 and Shiraishi, T. et al., 1998, International Jour US 2009/0270267 A1 Oct. 29, 2009 nal of Cancer, vol. 79, pp. 175-178; UCP2 gene (mitochon Thus, genes that can function as markers for metastatic drial uncoupling protein2) as described in WO 2003/076594; esophagus cancer can be predicted. UPK1A gene (uroplakin 1A) as described in WO 2003/ 0015. In order to solve the above problems, we analyzed 042661; and HSPA1B gene (heat shock 70 kDa protein 1) as the gene expression in an esophageal cancer tissue and in a described in Kawanishi, K. et al., 1999, Cancer, vol. 85, pp. non-cancerous tissue using a DNA array, whereby we have 1649-1657.
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