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

Manel Esteller, Egle Avizienyte, Paul G. Corn, Ragnhild A. Lothe, Stephen B Baylin, Lauri A. Aaltonen, James G. Herman

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)164-168
Number of pages5
JournalOncogene
Volume19
Issue number1
StatePublished - Jan 6 2000

Fingerprint

Peutz-Jeghers Syndrome
Epigenomics
decitabine
Methylation
Colorectal Neoplasms
Neoplasms
Genes
Carcinoma
Cell Line
CpG Islands
Hamartoma
Germ-Line Mutation
Papillary Carcinoma
Testicular Neoplasms
Pigmentation
Polyps
Tumor Cell Line
Tumor Suppressor Genes
Gastrointestinal Tract
Stomach

Keywords

  • Human cancer
  • hypermethylation
  • LKB1
  • Peutz-Jeghers

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Esteller, M., Avizienyte, E., Corn, P. G., Lothe, R. A., Baylin, S. B., Aaltonen, L. A., & Herman, J. G. (2000). Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome. Oncogene, 19(1), 164-168.

Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome. / Esteller, Manel; Avizienyte, Egle; Corn, Paul G.; Lothe, Ragnhild A.; Baylin, Stephen B; Aaltonen, Lauri A.; Herman, James G.

In: Oncogene, Vol. 19, No. 1, 06.01.2000, p. 164-168.

Research output: Contribution to journalArticle

Esteller, M, Avizienyte, E, Corn, PG, Lothe, RA, Baylin, SB, Aaltonen, LA & Herman, JG 2000, 'Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome', Oncogene, vol. 19, no. 1, pp. 164-168.
Esteller M, Avizienyte E, Corn PG, Lothe RA, Baylin SB, Aaltonen LA et al. Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome. Oncogene. 2000 Jan 6;19(1):164-168.
Esteller, Manel ; Avizienyte, Egle ; Corn, Paul G. ; Lothe, Ragnhild A. ; Baylin, Stephen B ; Aaltonen, Lauri A. ; Herman, James G. / Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome. In: Oncogene. 2000 ; Vol. 19, No. 1. pp. 164-168.
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