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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

132 Citaten (Scopus)


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.

Originele taal-2Engels
Pagina's (van-tot)407-14
Aantal pagina's8
TijdschriftHuman mutation
Nummer van het tijdschrift4
StatusGepubliceerd - apr. 2011
Extern gepubliceerdJa


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