Familial Cancer

, Volume 8, Issue 4, pp 421–429

Screening for germline mutations of MLH1, MSH2, MSH6 and PMS2 genes in Slovenian colorectal cancer patients: implications for a population specific detection strategy of Lynch syndrome

  • Gašper Berginc
  • Matej Bračko
  • Metka Ravnik-Glavač
  • Damjan Glavač

DOI: 10.1007/s10689-009-9258-4

Cite this article as:
Berginc, G., Bračko, M., Ravnik-Glavač, M. et al. Familial Cancer (2009) 8: 421. doi:10.1007/s10689-009-9258-4


Microsatellite instability (MSI) is present in more than 90% of colorectal cancers of patients with Lynch syndrome, and is therefore a feasible marker for the disease. Mutations in MLH1, MSH2, MSH6 and PMS2, which are one of the main causes of deficient mismatch repair and subsequent MSI, have been linked to the disease. In order to establish the role of each of the 4 genes in Slovenian Lynch syndrome patients, we performed MSI analysis on 593 unselected CRC patients and subsequently searched for the presence of point mutations, larger genomic rearrangements and MLH1 promoter hypermethylation in patients with MSI-high tumours. We detected 43 (7.3%) patients with MSI-H tumours, of which 7 patients (1.3%) harboured germline defects: 2 in MLH1, 4 in MSH2, 1 in PMS2 and none in MSH6. Twenty-nine germline sequence variations of unknown significance and 17 deleterious somatic mutations were found. MLH1 promoter methylation was detected in 56% of patients without detected germline defects and in 1 (14%) suspected Lynch syndrome. Due to the minor role of germline MSH6 mutations, we adapted the Lynch syndrome detection strategy for the Slovenian population of CRC patients, whereby germline alterations should be first sought in MLH1 and MSH2 followed by a search for larger genomic rearrangements in these two genes. When no germline mutations are found tumors should be further tested for the presence of germline defects in PMS2 and MSH6. The choice about which gene should be tested first can be guided more accurately by the immunohistochemical analysis. Our study demonstrates that the incidence of MMR mutations in a population should be known prior to the application of one of several suggested strategies for detection of Lynch syndrome.


Detection strategy Lynch syndrome Microsatellite instability Mismatch repair genes Mononucleotide microsatellite markers 



Microsatellite instability


Hereditary non-polyposis colorectal cancer


Colorectal cancer


Mismatch repair


High level of microsatellite instability


Low level of microsatellite instability


Microsatellite stable


Pentaplex mononucleotide repeat panel


Denaturating high performance liquid chromatography


Multiplex ligation-dependent probe amplification


Methylation specific MLPA


Exonic splice enhancers

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Gašper Berginc
    • 1
  • Matej Bračko
    • 2
  • Metka Ravnik-Glavač
    • 1
    • 3
  • Damjan Glavač
    • 1
  1. 1.Department of Molecular Genetics, Faculty of Medicine, Institute of PathologyUniversity of LjubljanaLjubljanaSlovenia
  2. 2.Department of PathologyInstitute of OncologyLjubljanaSlovenia
  3. 3.Faculty of Medicine, Institute of BiochemistryUniversity of LjubljanaLjubljanaSlovenia