Prospective evaluation of molecular screening for Lynch syndrome in patients with endometrial cancer ≤ 70 years

Gynecol Oncol. 2012 May;125(2):414-20. doi: 10.1016/j.ygyno.2012.01.049. Epub 2012 Feb 1.


Objective: Lynch syndrome (LS) is a hereditary syndrome that predisposes to multiple malignancies including endometrial cancer (EC). We aimed to evaluate a diagnostic strategy for LS based on routine analysis of microsatellite instability (MSI) and immunohistochemical (IHC) staining for mismatch repair (MMR) proteins in tumour tissue of all newly diagnosed EC patients ≤ 70 years.

Methods: Consecutive EC patients ≤ 70 years were included prospectively in eight Dutch centres. EC specimens were analysed for MSI, IHC of four MMR proteins, MMR gene methylation status and BRAF-mutations. tumours were classified as; 1) likely to be caused by LS, 2) sporadic MSI-H, or 3) microsatellite stable (MSS).

Results: Tumour specimens of 179 patients (median age 61 years, IQR 57-66) were analysed. In our study 92% of included patients were over 50 years of age. Eleven EC patients were found likely to have LS (6%; 95% CI 3-11%), including 1 patient suspected of an MLH1, 2 of an MSH2, 6 of an MSH6 and 2 of a PMS2 gene defect. Germline mutation analyses revealed 7 MMR gene germline mutations. Ten patients likely to have LS (92%) were older than 50 years. In addition, 31 sporadic MSI-H tumours with MLH1 promoter hypermethylation (17%; 95% CI 13-24%) were identified.

Conclusions: Molecular screening for LS in patients with EC diagnosed ≤ 70 years, leads to identification of a profile likely to have LS in 6% of cases. New screening guidelines for LS are needed, including recommendations for EC patients older than 50 years of age.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Aged
  • Carcinoma, Endometrioid / genetics
  • Carcinoma, Endometrioid / metabolism
  • Colorectal Neoplasms, Hereditary Nonpolyposis / diagnosis*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics
  • Colorectal Neoplasms, Hereditary Nonpolyposis / metabolism
  • DNA Repair Enzymes / genetics
  • DNA-Binding Proteins / genetics
  • Endometrial Neoplasms / genetics*
  • Endometrial Neoplasms / metabolism*
  • Female
  • Germ-Line Mutation
  • Humans
  • Immunohistochemistry
  • Microsatellite Instability
  • Middle Aged
  • Mismatch Repair Endonuclease PMS2
  • Prospective Studies
  • Proto-Oncogene Proteins B-raf / genetics


  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Adenosine Triphosphatases
  • PMS2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • DNA Repair Enzymes