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.

  • Short Report
  • Published:

Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome

Oncogene volume 19, pages 164–168 (2000)Cite this article

Abstract

Germ-line mutations of the LKB1 gene cause Peutz-Jeghers syndrome (PJS) characterized by mucocutaneous pigmentation, predisposition to benign hamartomas of the gastrointestinal tract and also to several types of tumors. However, somatic mutations of this gene are very rare. To examine inactivation of LKB1 by epigenetic mechanisms, we investigated a series of primary tumors and cancer cell lines, for hypermethylation affecting the CpG island located in the 5′ region of the LKB1 gene using Methylation-specific PCR (MSP). First, we screened 51 cancer cell lines. Only three colorectal and one cervical carcinoma cell lines were methylated at LKB1, and loss of the LKB1 transcript was demonstrated. Treatment with the demethylating agent 5-aza-2′-deoxycytidine restored LKB1 expression. To address the incidence of LKB1 epigenetic inactivation in primary tumors, we analysed colorectal, breast, gastric, pancreatic, thyroid, bladder and testicular carcinomas (n=195). Normal tissues from the mentioned organs were unmethylated in this region. Among the described tumors, only one colorectal carcinoma and three testicular tumors displayed LKB1 promoter hypermethylation. Further study of those histological types more commonly associated with PJS, demonstrated that LKB1 promoter hypermethylation was present in five of 11 (45%) papillary breast carcinomas. Finally, in three patients with a strong family story suggestive of PJS disease, abnormal LKB1 methylation was found in four of 22 (18%) hamartomatous polyps lesions. Our findings provide an alternative pathway for inactivation of the LKB1 tumor suppressor gene involving promoter hypermethylation.

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

Similar content being viewed by others

References

  • Avizienyte E, Loukola A, Roth S, Hemminki A, Tarkkanen M, Salovaara R, Arola J, Butzow R, Husgafvel-Pursiainen K, Kokkola A, Jarvinen H and Aaltonen LA . 1999 Am J Pathol 154: 677–681.

  • Avizienyte E, Roth S, Loukola A, Hemminki A, Lothe RA, Stenwig AE, Fossam SD, Salovaara R and Aaltonen, LA . 1998 Cancer Res 58: 2087–2090.

  • Baylin SB, Herman JG, Graff JR, Vertino PM and Issa JP . 1998 Adv Cancer Res 72: 141–196.

  • Bignell GR, Barfoot R, Seal S, Collins N, Warren W and Stratton MR . 1998 Cancer Res 5: 1384–1386.

  • Boardman LA, Thibodeau SN, Schaid DJ, Lindor NM, McDonnell SK, Burgart LJ, Ahlquist DA, Podratz KC, Pittelkow M and Hartmann LC . 1988 Ann Inter Med 128: 896–899.

  • Dong SM, Kim KM, Kim SY, Shin MS, Na EY, Lee SH, Park WS, Yoo NJ, Jang JJ, Yoon CY, Kim JW, Kim SY, Yang YM, Kim SH, Kim CS and Lee JY . 1998 Cancer Res 58: 3787–3790.

  • Esteller M, Corn PG, Urena JM, Gabrielson E, Baylin SB and Herman JG . 1998a Cancer Res 58: 4515–4518.

  • Esteller M, Garcia A, Martinez-Palones JM, Xercavins J and Reventos J . 1999b Am J Clin Pathol 1113: 336–342.

    Article  CAS  Google Scholar 

  • Esteller M, Hamilton SR, Burger PC, Baylin SB and Herman JG . 1999a Cancer Res 59: 793–797.

  • Esteller M, Levine R, Baylin SB, Ellenson LH and Herman JG . 1998b Oncogene 17: 2413–2417.

  • Giardiello FM, Welsh SB, Hamilton SR, Offerhaus GJ, Gittelsohn AM, Booker SV, Krush AJ, Yardley JH and Luk GD . 1987 N Engl J Med 316: 1511–1514.

    Article  CAS  Google Scholar 

  • Gruber SB, Entius MM, Petersen GM, Laken SJ, Long PA, Boyer R, Levin AM, Mujumdar UJ, Trent JM, Kinzler KW, Vogelstein B, Hamilton SR, Polymeropoulos MH, Offerhaus GJ and Giardiello FM . 1998 Cancer Res 58: 5267–5270.

  • Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, Bignell G, Warren W, Aminoff M, Hoglund P, Jarvinen H, Kristo P, Pelin K, Ridanpaa M, Salovaara R, Toro T, Bodmer W, Olschwang S, Olsen AS, Stratton MR, de la Chapelle A and Aaltonen LA . 1998 Nature 391: 184–187.

    Article  CAS  Google Scholar 

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

  • Herman JG, Jen J, Merlo A and Baylin SB . 1996b Cancer Res 56: 722–727.

  • Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, Markowitz S, Willson JK, Hamilton SR, Kinzler KW, Kane MF, Kolodne, RD, Vogelstein B, Kunkel TA and Bayli SB . 1998 Proc Natl Acad Sci USA 95: 6870–6875.

  • Jenne DE, Reimann H, Nezu, J, Friedel W, Loff S, Jeschke R, Muller O, Back W and Zimmer M . 1998 Nat Genet 18: 38–43.

    Article  CAS  Google Scholar 

  • Jones Jr HW, McKusick VA, Harper PS and Wuu KD . 1971 Obstet Gynecol 38: 945–949.

  • Jones PA and Laird PW . 1999 Nat Genet 21: 163–167.

    Article  CAS  Google Scholar 

  • Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, Jessup JM and Kolodner R . 1997 Cancer Res 57: 808–811.

  • Lee JY, Dong SM, Kim HS, Kim SY, Na EY, Shin MS, Lee SH, Park WS, Kim KM, Lee YS, Jang JJ and Yoo NJ . 1998 Cancer Res 58: 1140–1143.

  • Mehenni H, Gehrig C, Nez, J, Oku A, Shimane M, Rossier C, Guex N, Blouin JL, Scott HS and Antonarakis SE . 1998 Am J Hum Genet 63: 1641–1650.

  • Resta N, Simone C, Mareni C, Montera M, Gentile M, Susca F, Gristina R, Pozzi S, Bertario L, Bufo P, Carlomagno N, Ingrosso M, Rossini FP, Tenconi R and Guanti G . 1998 Cancer Res 58: 4799–4801.

  • Riley E and Swift M . 1980 Cancer 46: 815–817.

    Article  CAS  Google Scholar 

  • Tomlinson IP and Houlston RS . 1997 J Med Genet 34: 1007–1011.

  • Tompkins WA, Watrach AM, Schmale JD, Schultz RM and Harris JA . 1974 J Natl Cancer Inst 52: 1101–1110.

  • Vermeulen SJ, Chen TR, Speleman F, Nollet F, Van Roy FM and Mareel MM . 1998 Cancer Genet Cytogenet 107: 76–79.

  • Wang ZJ, Taylor F, Churchman M, Norbury G and Tomlinson I . 1998 Am J Pathol 153: 363–366.

  • Ylikorkala A, Avizienyte E, Tomlinson IPM, Tiainen M, Roth S, Loukola A, Hemminki A, Johansson M, Sistonen P, Markie D, Neale K, Phillips R, Zauber P, Twama T, Sampson J, Jarvinen H, Makela TP and Aaltonen LA . 1999 Hum Mol Genet 8: 45–51.

Download references

Acknowledgements

The authors thank Enrique Lerma, Jaime Prat, Xavier Matias-Guiu,, Francesc Treserra, Angel Garcia and Sophie D Fossa for providing tumor samples. M Esteller is a recipient of a Spanish Ministerio de Educacion y Cultura Award. JG Herman is a Valvano Scholar. SB Baylin and JG Herman receive research funding and are entitled to sales royalties from ONCOR, which is developing products related to research described in this paper. The terms of this arrangement have been reviewed and approved by The Johns Hopkins University in accordance with its conflict of interest policies.

Author information

Authors and Affiliations

  1. Tumor Biology, The Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, 21231, Maryland, MD, USA

    Manel Esteller, Paul G Corn, Stephen B Baylin & James G Herman

  2. Department of Medical Genetics, Haartman Institute, PO Box 21, (Haartmaninkatu 3), 00014 University of Helsinki, Finland

    Egle Avizienyte & Lauri A Aaltonen

  3. Department of Genetics, Institute of Cancer Research, The Norwegian Radium Hospital, 0310 Oslo, Norway

    Ragnhild A Lothe

Authors
  1. Manel Esteller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Egle Avizienyte
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul G Corn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ragnhild A Lothe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephen B Baylin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lauri A Aaltonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. James G Herman
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Esteller, M., Avizienyte, E., Corn, P. et al. Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome. Oncogene 19, 164–168 (2000). https://doi.org/10.1038/sj.onc.1203227

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203227

Keywords

This article is cited by

Search

Advanced search

Quick links