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  • Oncogenomics
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Identification of 27 5′ CpG islands aberrantly methylated and 13 genes silenced in human pancreatic cancers

Oncogene volume 23, pages 8705–8710 (2004)Cite this article

Abstract

Aberrantly methylated DNA fragments were searched for in human pancreatic cancers, using the genome scanning technique: methylation-sensitive-representational difference analysis (MS-RDA). MS-RDA isolated 111 DNA fragments derived from CpG islands (CGIs), and 35 of them were from CGIs in the 5′ regions of known genes. Methylation-specific PCR (MSP) of the CGIs in seven pancreatic cancer cell lines and two pancreatic ductal epithelial cell lines showed that 27 CGIs in the 5′ regions were aberrantly methylated in at least one of the cancer cell lines. Quantitative reverse-transcription–PCR analysis showed that downstream genes of all the CGIs were either not expressed or only very weakly expressed in cancer cell lines with the aberrant methylation. In the pancreatic ductal epithelial cell lines, 18 genes were expressed at various levels, and nine genes were not expressed at all. Treatment of a cancer cell line with a demethylating agent, 5-aza-2′-deoxycytidine, restored the expression of 13 genes, RASGRF2, ADAM23, NEF3, NKX2-8, HAND1, EGR4, PRG2, FBN2, CDH2, TLL1, NPTX1, NTSR1 and THBD, showing their silencing by methylation of their 5′ CGIs. MSP of 24 primary pancreatic cancers showed that all these genes, except for THBD, were methylated in at least one cancer. Some of those were suggested to be potentially involved in pancreatic cancer development and progression.

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Abbreviations

CGI:

CpG island

MS-RDA:

methylation-sensitive representational difference analysis

MSP:

methylation-specific PCR

RT–PCR:

reverse-transcription–PCR

5-aza-dC:

5-aza-2′-deoxycytidine

References

  • Agathanggelou A, Bieche I, Ahmed-Choudhury J, Nicke B, Dammann R, Baksh S, Gao B, Minna JD, Downward J, Maher ER and Latif F . (2003). Cancer Res., 63, 5344–5351.

  • Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N and Perucho M . (1988). Cell, 53, 549–554.

  • Arozarena I, Matallanas D, Berciano MT, Sanz-Moreno V, Calvo F, Munoz MT, Egea G, Lafarga M and Crespo P . (2004). Mol. Cell. Biol., 24, 1516–1530.

  • Asada K, Miyamoto K, Fukutomi T, Tsuda H, Yagi Y, Wakazono K, Oishi S, Fukui H, Sugimura T and Ushijima T . (2003). Oncology, 64, 380–388.

  • Bardeesy N and DePinho RA . (2002). Nat. Rev. Cancer, 2, 897–909.

  • Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ and Kern SE . (1994). Nat. Genet., 8, 27–32.

  • Clark TG, Conway SJ, Scott IC, Labosky PA, Winnier G, Bundy J, Hogan BL and Greenspan DS . (1999). Development, 126, 2631–2642.

  • Costa FF, Verbisck NV, Salim AC, Ierardi DF, Pires LC, Sasahara RM, Sogayar MC, Zanata SM, Mackay A, O'Hare M, Soares F, Simpson AJ and Camargo AA . (2004). Oncogene, 23, 1481–1488.

  • Furukawa T, Duguid WP, Rosenberg L, Viallet J, Galloway DA and Tsao MS . (1996). Am. J. Pathol., 148, 1763–1770.

  • Griffin CA, Hruban RH, Long PP, Morsberger LA, Douna-Issa F and Yeo CJ . (1994). Genes Chromosomes Cancer, 9, 93–100.

  • Hahn SA, Schutte M, Hoque AT, Moskaluk CA, Da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH and Kern SE . (1996). Science, 271, 350–353.

  • Herman JG, Merlo A, Mao L, Lapidus RG, Issa JP, Davidson NE, Sidransky D and Baylin SB . (1995). Cancer Res., 55, 4525–4530.

  • Horikoshi N, Cong J, Kley N and Shenk T . (1999). Biochem. Biophys. Res. Commun., 261, 864–869.

  • Jemal A, Murray T, Samuels A, Ghafoor A, Ward E and Thun MJ . (2003). CA Cancer J. Clin., 53, 5–26.

  • Julien JP and Mushynski WE . (1998). Prog. Nucleic Acid Res. Mol. Biol., 61, 1–23.

  • Kaneda A, Kaminishi M, Yanagihara K, Sugimura T and Ushijima T . (2002). Cancer Res., 62, 6645–6650.

  • Kaneda A, Takai D, Kaminishi M, Okochi E and Ushijima T . (2003). Ann. NY Acad. Sci., 983, 131–141.

  • Lisitsyn N and Wigler M . (1993). Science, 259, 946–951.

  • Liu N, Furukawa T, Kobari M and Tsao MS . (1998). Am. J. Pathol., 153, 263–269.

  • Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB and Sidransky D . (1995). Nat. Med., 1, 686–692.

  • Mitchell MS, Kan-Mitchell J, Minev B, Edman C and Deans RJ . (2000). Cancer Res., 60, 6448–6456.

  • Miyamoto K, Asada K, Fukutomi T, Okochi E, Yagi Y, Hasegawa T, Asahara T, Sugimura T and Ushijima T . (2003). Oncogene, 22, 274–280.

  • Omeis IA, Hsu YC and Perin MS . (1996). Genomics, 36, 543–545.

  • Paz MF, Wei S, Cigudosa JC, Rodriguez-Perales S, Peinado MA, Huang TH and Esteller M . (2003). Hum. Mol. Genet., 12, 2209–2219.

  • Qiu C, Yu M, Shan L and Snyderwine EG . (2003). Oncogene, 22, 1253–1260.

  • Riley P, Anson-Cartwright L and Cross JC . (1998). Nat. Genet., 18, 271–275.

  • Rozenblum E, Schutte M, Goggins M, Hahn SA, Panzer S, Zahurak M, Goodman SN, Sohn TA, Hruban RH, Yeo CJ and Kern SE . (1997). Cancer Res., 57, 1731–1734.

  • Sato N, Fukushima N, Maitra A, Matsubayashi H, Yeo CJ, Cameron JL, Hruban RH and Goggins M . (2003). Cancer Res., 63, 3735–3742.

  • Takai D and Jones PA . (2002). Proc. Natl. Acad. Sci. USA, 99, 3740–3745.

  • Takai D, Yagi Y, Wakazono K, Ohishi N, Morita Y, Sugimura T and Ushijima T . (2001). Oncogene, 20, 7505–7513.

  • Tourtellotte WG, Nagarajan R, Auyeung A, Mueller C and Milbrandt J . (1999). Development, 126, 5061–5071.

  • Toyota M, Ho C, Ahuja N, Jair KW, Li Q, Ohe-Toyota M, Baylin SB and Issa JP . (1999). Cancer Res., 59, 2307–2312.

  • Ueki T, Toyota M, Skinner H, Walter KM, Yeo CJ, Issa JP, Hruban RH and Goggins M . (2001). Cancer Res., 61, 8540–8546.

  • Ueki T, Toyota M, Sohn T, Yeo CJ, Issa JP, Hruban RH and Goggins M . (2000). Cancer Res., 60, 1835–1839.

  • Ushijima T, Morimura K, Hosoya Y, Okonogi H, Tatematsu M, Sugimura T and Nagao M . (1997). Proc. Natl. Acad. Sci. USA, 94, 2284–2289.

  • Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, Yeo CJ, Kern SE and Hruban RH . (2000). Cancer Res., 60, 2002–2006.

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Acknowledgements

The authors are grateful to Drs M Sakamoto and B Nakata for providing tumor samples; and to Dr N McDonell for critical reading of the manuscript. This work was supported by Grants-in-Aid for the Second-term Comprehensive 10-Year Strategy for Cancer Control; by the Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan; and by a Grant from the Foundation for Promotion of Cancer Research. AH and JF are recipients of Research Resident Fellowships from the Foundation for Promotion of Cancer Research.

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Authors and Affiliations

  1. Carcinogenesis Division, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo, 104-0045, Japan

    Atsushi Hagihara, Kazuaki Miyamoto, Junichi Furuta, Kuniko Wakazono, Takashi Sugimura & Toshikazu Ushijima

  2. Department of Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan

    Atsushi Hagihara & Shoji Fukushima

  3. Department of Internal Medicine, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan

    Atsushi Hagihara & Shuichi Seki

  4. Pathology Division, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo, 104-0045, Japan

    Nobuyoshi Hiraoka

  5. Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, M5G 2M9, Ontario, Canada

    Ming-Sound Tsao

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  1. Atsushi Hagihara
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Correspondence to Toshikazu Ushijima.

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Supplementary information is available at ONC reports online (http://www.nature.com/onc)

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Hagihara, A., Miyamoto, K., Furuta, J. et al. Identification of 27 5′ CpG islands aberrantly methylated and 13 genes silenced in human pancreatic cancers. Oncogene 23, 8705–8710 (2004). https://doi.org/10.1038/sj.onc.1207783

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