Recurrence and variability of germline EPCAM deletions in Lynch syndrome

Roland P Kuiper, Lisenka E L M Vissers, Ramprasath Venkatachalam, Danielle Bodmer, Eveline Hoenselaar, Monique Goossens, Aline Haufe, Eveline Kamping, Renée C Niessen, Frans B L Hogervorst, Johan J P Gille, Bert Redeker, Carli M J Tops, Marielle E van Gijn, Ans M W van den Ouweland, Nils Rahner, Verena Steinke, Philip Kahl, Elke Holinski-Feder, Monika MorakMatthias Kloor, Susanne Stemmler, Beate Betz, Pierre Hutter, David J Bunyan, Sapna Syngal, Julie O Culver, Tracy Graham, Tsun L Chan, Iris D Nagtegaal, J Han J M van Krieken, Hans K Schackert, Nicoline Hoogerbrugge, Ad Geurts van Kessel, Marjolijn J L Ligtenberg

Research output: Contribution to journalArticlepeer-review


Recently, we identified 3' end deletions in the EPCAM gene as a novel cause of Lynch syndrome. These truncating EPCAM deletions cause allele-specific epigenetic silencing of the neighboring DNA mismatch repair gene MSH2 in tissues expressing EPCAM. Here we screened a cohort of unexplained Lynch-like families for the presence of EPCAM deletions. We identified 27 novel independent MSH2-deficient families from multiple geographical origins with varying deletions all encompassing the 3' end of EPCAM, but leaving the MSH2 gene intact. Within The Netherlands and Germany, EPCAM deletions appeared to represent at least 2.8% and 1.1% of the confirmed Lynch syndrome families, respectively. MSH2 promoter methylation was observed in epithelial tissues of all deletion carriers tested, thus confirming silencing of MSH2 as the causative defect. In a total of 45 families, 19 different deletions were found, all including the last two exons and the transcription termination signal of EPCAM. All deletions appeared to originate from Alu-repeat mediated recombination events. In 17 cases regions of microhomology around the breakpoints were found, suggesting nonallelic homologous recombination as the most likely mechanism. We conclude that 3' end EPCAM deletions are a recurrent cause of Lynch syndrome, which should be implemented in routine Lynch syndrome diagnostics.

Original languageEnglish
Pages (from-to)407-14
Number of pages8
JournalHuman mutation
Issue number4
Publication statusPublished - Apr 2011
Externally publishedYes


  • Antigens, Neoplasm/genetics
  • Base Sequence
  • Cell Adhesion Molecules/genetics
  • Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
  • DNA Methylation
  • Epithelial Cell Adhesion Molecule
  • Genetic Variation
  • Germ-Line Mutation/genetics
  • Models, Genetic
  • Molecular Sequence Data
  • MutS Homolog 2 Protein/genetics
  • Netherlands
  • Promoter Regions, Genetic
  • Recurrence
  • Sequence Deletion/genetics


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