Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Oncogenomics
  • Published:

Frequent RASSF1A promoter hypermethylation and K-ras mutations in pancreatic carcinoma

Oncogene volume 22, pages 3806–3812 (2003)Cite this article

Abstract

Recently, we have characterized the Ras association domain family 1A gene (RASSF1A) at the segment 3p21.3, which is frequently lost in variety of human cancers and epigenetically inactivated in many types of primary tumors, such as lung, breast, kidney, prostate and thyroid carcinomas. Here, we investigated the methylation status of the RASSF1A CpG island promoter in the pathogenesis of pancreatic cancer. RASSF1A hypermethylation was detected in 29 out of 45 (64%) primary adenocarcinomas, in 10 out of 12 (83%) endocrine tumors and in eight out of 18 (44%) pancreatitis samples. In seven out of eight pancreas cancer cell lines, RASSF1A was silenced and was retranscribed after treatment with 5-aza-2′-deoxycytidine. Additionally, we analysed the aberrant methylation frequency of cell cycle inhibitor p16INK4a and K-ras gene mutations in the pancreatic samples. p16 inactivation was detected in 43% of adenocarcinomas, in 17% of neuroendocrine tumors, in 18% of pancreatitis and in 63% of pancreas cancer cell lines. K-ras mutations were detected in 16 out of 45 (36%) primary adenocarcinomas. Pancreatic adenocarcinomas with K-ras mutation have significantly less RASSF1A methylation and vice versa (P=0.001, χ2 test). In conclusion, our data indicate that inactivation of the RASSF1A gene is a frequent event in pancreatic cancer and suggest an inverse correlation between RASSF1A silencing and K-ras activation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

Abbreviations

RASSF1:

Ras association domain family 1 gene

PanIN:

pancreatic intraepithelial neoplasia

LOH:

loss of heterozygosity

5-Aza-CdR:

5-aza-2′-deoxycytidine

MSP:

methylation-specific PCR

TNM:

tumor-node-metastasis

SSCP:

single-strand conformation polymorphism

WT:

wild type

References

  • Agathanggelou A, Honorio S, Macartney DP, Martinez A, Dallol A, Rader J, Fullwood P, Chauhan A, Walker R, Shaw JA, Hosoe S, Lerman MI, Minna JD, Maher ER and Latif F . (2001). Oncogene, 20, 1509–1518.

  • Ahuja N, Li Q, Mohan AL, Baylin SB and Issa JP . (1998). Cancer Res., 58, 5489–5494.

  • Barghorn A, Komminoth P, Bachmann D, Rutimann K, Saremaslani P, Muletta-Feurer S, Perren A, Roth J, Heitz PU and Speel EJ . (2001). J. Pathol., 194, 451–458.

  • Bos JL . (1989). Cancer Res., 49, 4682–4689.

  • Burbee DG, Forgacs E, Zochbauer-Muller S, Shivakumar L, Fong K, Gao B, Randle D, Kondo M, Virmani A, Bader S, Sekido Y, Latif F, Milchgrub S, Toyooka S, Gazdar AF, Lerman MI, Zabarovsky E, White M and Minna JD . (2001). J. Natl. Cancer Inst., 93, 691–699.

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

  • Chan AO, Kim SG, Bedeir A, Issa JP, Hamilton SR and Rashid A . (2003). Oncogene, 22, 924–934.

  • Chang MC, Chang YT, Wu MS, Shun CT, Tien YW and Lin JT . (2001). J. Formos Med. Assoc., 100, 352–354.

  • Clark SJ, Harrison J, Paul CL and Frommer M . (1994). Nucleic Acids Res., 22, 2990–2997.

  • Dammann R, Li C, Yoon JH, Chin PL, Bates S and Pfeifer GP . (2000). Nat. Genet., 25, 315–319.

  • Dammann R, Schagdarsurengin U, Strunnikova M, Rastetter M, Seidel C, Liu L, Tommasi S and Pfeifer GP . (2003). Histol. Histopathol., 18, 665–677.

  • Dammann R, Takahashi T and Pfeifer GP . (2001a). Oncogene, 20, 3563–3567.

  • Dammann R, Yang G and Pfeifer GP . (2001b). Cancer Res., 61, 3105–3109.

  • Fukushima N, Sato N, Ueki T, Rosty C, Walter KM, Wilentz RE, Yeo CJ, Hruban RH and Goggins M . (2002). Am. J. Pathol., 160, 1573–1581.

  • Furuya N, Kawa S, Akamatsu T and Furihata K . (1997). Gastroenterology, 113, 593–598.

  • Greenlee RT, Hill-Harmon MB, Murray T and Thun M . (2001). CA Cancer J. Clin., 51, 15–36.

  • Gunzburg WH and Salmons B . (2001). Trends Mol. Med., 7, 30–37.

  • Hahn SA, Seymour AB, Hoque AT, Schutte M, da Costa LT, Redston MS, Caldas C, Weinstein CL, Fischer A and Yeo CJ . (1995). Cancer Res., 55, 4670–4675.

  • Herman JG, Graff JR, Myohanen S, Nelkin BD and Baylin SB . (1996). Proc. Natl. Acad. Sci. USA, 93, 9821–9826.

  • Hruban RH, Offerhaus GJ, Kern SE, Goggins M, Wilentz RE and Yeo CJ . (1998). J. Hepatobiliary Pancreat. Surg., 5, 383–391.

  • Hruban RH, van Mansfeld AD, Offerhaus GJ, van Weering DH, Allison DC, Goodman SN, Kensler TW, Bose KK, Cameron JL and Bos JL . (1993). Am. J. Pathol., 143, 545–554.

  • Hruban RH, Wilentz RE and Kern SE . (2000). Am. J. Pathol., 156, 1821–1825.

  • Hsieh CJ, Klump B, Holzmann K, Borchard F, Gregor M and Porschen R . (1998). Cancer Res., 58, 3942–3945.

  • Issa JP, Ahuja N, Toyota M, Bronner MP and Brentnall TA . (2001). Cancer Res., 61, 3573–3577.

  • Jones PA and Taylor SM . (1980). Cell, 20, 85–93.

  • Khokhlatchev A, Rabizadeh S, Xavier R, Nedwidek M, Chen T, Zhang X, Seed B and Avruch J . (2002). Curr. Biol., 12, 253–265.

  • Kita K, Saito S, Morioka CY and Watanabe A . (1999). Int. J. Cancer, 80, 553–558.

  • Kok K, Naylor SL and Buys CH . (1997). Adv. Cancer Res., 71, 27–92.

  • Kuzmin I, Gillespie JW, Protopopov A, Geil L, Dreijerink K, Yang Y, Vocke CD, Duh FM, Zabarovsky E, Minna JD, Rhim JS, Emmert-Buck MR, Linehan WM and Lerman MI . (2002). Cancer Res., 62, 3498–3502.

  • Kwong J, Lo KW, To KF, Teo PM, Johnson PJ and Huang DP . (2002). Clin. Cancer Res., 8, 131–137.

  • Laghi L, Orbetegli O, Bianchi P, Zerbi A, Di Carlo V, Boland CR and Malesci A . (2002). Oncogene, 21, 4301–4306.

  • Lerman MI and Minna JD . (2000). Cancer Res., 60, 6116–6133.

  • Liu L, Yoon JH, Dammann R and Pfeifer GP . (2002). Oncogene, 21, 6835–6840.

  • Moore PS, Zamboni G, Brighenti A, Lissandrini D, Antonello D, Capelli P, Rigaud G, Falconi M and Scarpa A . (2001). Am. J. Pathol., 158, 317–321.

  • Muscarella P, Melvin WS, Fisher WE, Foor J, Ellison EC, Herman JG, Schirmer WJ, Hitchcock CL, DeYoung BR and Weghorst CM . (1998). Cancer Res., 58, 237–240.

  • Ortiz-Vega S, Khokhlatchev A, Nedwidek M, Zhang XF, Dammann R, Pfeifer GP and Avruch J . (2002). Oncogene, 21, 1381–1390.

  • Perugini RA, McDade TP, Vittimberga Jr FJ and Callery MP . (1998). Crit. Rev. Eukaryot. Gene Expr., 8, 377–393.

  • Pfeifer GP, Yoon JH, Liu L, Tommasi S, Wilczynski SP and Dammann R . (2002). Biol. Chem., 383, 907–914.

  • Sato T, Konishi K, Kimura H, Maeda K, Yabushita K, Tsuji M and Miwa A . (2000). Hepatogastroenterology, 47, 875–879.

  • Schagdarsurengin U, Gimm O, Hoang-Vu C, Dralle H, Pfeifer GP and Dammann R . (2002). Cancer Res., 62, 3698–3701.

  • Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK, Moskaluk CA, Hahn SA, Schwarte-Waldhoff I, Schmiegel W, Baylin SB, Kern SE and Herman JG . (1997). Cancer Res., 57, 3126–3130.

  • Shivakumar L, Minna J, Sakamaki T, Pestell R and White MA . (2002). Mol. Cell. Biol., 22, 4309–4318.

  • Smiraglia DJ, Rush LJ, Fruhwald MC, Dai Z, Held WA, Costello JF, Lang JC, Eng C, Li B, Wright FA, Caligiuri MA and Plass C . (2001). Hum. Mol. Genet., 10, 1413–1419.

  • Tada M, Ohashi M, Shiratori Y, Okudaira T, Komatsu Y, Kawabe T, Yoshida H, Machinami R, Kishi K and Omata M . (1996). Gastroenterology, 110, 227–231.

  • Tada M, Omata M and Ohto M . (1991). Cancer, 67, 634–637.

  • Tomizawa Y, Kohno T, Kondo H, Otsuka A, Nishioka M, Niki T, Yamada T, Maeshima A, Yoshimura K, Saito R, Minna JD and Yokota J . (2002). Clin. Cancer Res., 8, 2362–2368.

  • van Engeland M, Roemen GM, Brink M, Pachen MM, Weijenberg MP, de Bruine AP, Arends JW, van den Brandt PA, de Goeij AF and Herman JG . (2002). Oncogene, 21, 3792–3795.

  • Vos MD, Ellis CA, Bell A, Birrer MJ and Clark GJ . (2000). J. Biol. Chem., 275, 35669–35672.

  • Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M, Johnson K, Tascilar M, Offerhaus GJ, Hruban RH and Kern SE . (2000). Am. J. Pathol., 156, 1641–1651.

  • Yamamoto H, Itoh F, Nakamura H, Fukushima H, Sasaki S, Perucho M and Imai K . (2001). Cancer Res., 61, 3139–3144.

  • Yoon JH, Dammann R and Pfeifer GP . (2001). Int. J. Cancer, 94, 212–217.

Download references

Acknowledgements

We thank Christel Trümpler and Kathrin Hammje for technical assistance. This work was supported by Grants NIH-CA88873 to GPP, Land Sachsen-Anhalt to CH-V, DFG-SFB518 to BOB and BMBF-FKZ01ZZ0104 to RD.

Author information

Authors and Affiliations

  1. AG Tumorgenetik der Medizinischen Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, 06097, Germany

    Reinhard Dammann, Undraga Schagdarsurengin & Noreen Otto

  2. Department of Biology, Beckman Research Institute, City of Hope Cancer Center, Duarte, 91010, CA, USA

    Limin Liu & Gerd P Pfeifer

  3. Universitätsklinik und Poliklinik für Allgemein-, Viszeral- und Gefäßchirurgie, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, 06097, Germany

    Oliver Gimm, Henning Dralle & Cuong Hoang-Vu

  4. Division of Endocrinology, Department of Internal Medicine, University of Ulm, Robert-Koch-Strasse 8, Ulm/Donau, 89070, Germany

    Bernhard O Boehm

Authors
  1. Reinhard Dammann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Undraga Schagdarsurengin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Limin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Noreen Otto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Oliver Gimm
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Henning Dralle
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bernhard O Boehm
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gerd P Pfeifer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Cuong Hoang-Vu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Reinhard Dammann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dammann, R., Schagdarsurengin, U., Liu, L. et al. Frequent RASSF1A promoter hypermethylation and K-ras mutations in pancreatic carcinoma. Oncogene 22, 3806–3812 (2003). https://doi.org/10.1038/sj.onc.1206582

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206582

Keywords

This article is cited by

Search

Advanced search

Quick links