Clinical & Experimental Metastasis

, Volume 29, Issue 8, pp 889–900 | Cite as

hMLH1 promoter hypermethylation and MSI status in human endometrial carcinomas with and without metastases

  • J. Bischoff
  • A. Ignatov
  • A. SemczukEmail author
  • C. Schwarzenau
  • T. Ignatov
  • T. Krebs
  • D. Küster
  • D. Przadka-Rabaniuk
  • A. Roessner
  • S. D. Costa
  • R. Schneider-Stock
Research Paper


We investigated the methylation status of mismatch repair gene hMLH1 in 80 primary human endometrial carcinomas (ECs) and in 30 metastatic lesions. It was correlated to the expression of hMLH1 protein, microsatellite instability (MSI) of ECs and to the well-known clinico-pathological variables of cancer. The hMLH1 promoter methylation was detected in 24 out of 64 (37.5 %) primary ECs but only in one out of 18 (5.6 %) metastatic lesions investigated. Promoter hMLH1 hypermethylation was found more often in early stage ECs and was associated with a decrease of hMLH1 protein expression immunohistochemically. An inverse relationship between hMLH1 expression and clinical stage of the disease was found (p = 0.048). Interestingly, there was a significant correlation between MSI and hMLH1 protein expression level (p = 0.042). MSI phenotype was found more often in EC metastases compared to the primary tumors (66.7 % vs 29.3 %; p = 0.039). However, neither hMLH1 promoter hypermethylation nor MSI was independent predictive factors for patient’s outcome. Using an in vitro model we showed that hMLH1 methylation is reversible. These data showed that hMLH1 methylation with a consequent protein decrease occurred early during EC tumorigenesis and may cause a MSI phenotype, which occurs relatively late. MSI may be an important mechanism supporting further the tumor progression. These findings may have importance for the specific chemosensitization of the primary tumors/metastases and can improve our understanding of endometrial carcinogenesis in humans.


Endometrial cancer Metastasis hMLH1 MSI Patient prognosis 



Endometrial cancer


International Federation of Gynecology and Obstetrics


Mismatch repair


Methylation-specific PCR


Microsatellite instability


Tumor suppressor gene


World Health Organization



We thank Dr. E. Erbstößer, Dr. K. Hellwig and Dr. M. Löttge for providing us paraffin-embedded specimens. We are grateful to the whole team of the laboratory of immunohistochemistry the staff of the Department of Pathology, Otto-von-Guericke University, Magdeburg, Germany, and the Department of Pathology, Lublin Medical University, Lublin, Poland, for the excellent technical assistance. This work was supported by NBL3-2 by the BMBF (Förderkennzeichen 01ZZ0407).

Conflict of interest

The authors declare that there are no conflicts of interest.

Supplementary material

10585_2012_9478_MOESM1_ESM.ppt (141 kb)
Fig. 1: Patient survival dependent on hMLH1 methylated status. A) Overall survival in all cohort, B) Progression-free survival in all cohort, C) Overall survival in early stage endometrial carcinoma (FIGO I/II), D) Progression-free survival in early stage endometrial carcinoma (FIGO I/II). Broken line represents the methylated cases, unbroken line represents the unmethylated cases. (PPT 141 kb)


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Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • J. Bischoff
    • 1
  • A. Ignatov
    • 1
  • A. Semczuk
    • 2
    Email author
  • C. Schwarzenau
    • 1
  • T. Ignatov
    • 1
  • T. Krebs
    • 3
  • D. Küster
    • 3
  • D. Przadka-Rabaniuk
    • 2
  • A. Roessner
    • 3
  • S. D. Costa
    • 1
  • R. Schneider-Stock
    • 4
  1. 1.Department of GynecologyOtto-von-Guericke UniversityMagdeburgGermany
  2. 2.IInd Department of GynecologyLublin Medical UniversityLublinPoland
  3. 3.Department of PathologyOtto-von-Guericke UniversityMagdeburgGermany
  4. 4.Department of PathologyNurnberg-Erlangen UniversityErlangenGermany

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