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Recurrence and variability of germline EPCAM deletions in Lynch syndrome
Author(s) -
Kuiper Roland P.,
Vissers Lisenka E.L.M.,
Venkatachalam Ramprasath,
Bodmer Danielle,
Hoenselaar Eveline,
Goossens Monique,
Haufe Aline,
Kamping Eveline,
Niessen Renée C.,
Hogervorst Frans B.L.,
Gille Johan J.P.,
Redeker Bert,
Tops Carli M.J.,
van Gijn Marielle E.,
van den Ouweland Ans M.W.,
Rahner Nils,
Steinke Verena,
Kahl Philip,
HolinskiFeder Elke,
Morak Monika,
Kloor Matthias,
Stemmler Susanne,
Betz Beate,
Hutter Pierre,
Bunyan David J.,
Syngal Sapna,
Culver Julie O.,
Graham Tracy,
Chan Tsun L.,
Nagtegaal Iris D.,
van Krieken J. Han J.M,
Schackert Hans K.,
Hoogerbrugge Nicoline,
van Kessel Ad Geurts,
Ligtenberg Marjolijn J.L.
Publication year - 2011
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21446
Subject(s) - lynch syndrome , msh2 , biology , non allelic homologous recombination , genetics , breakpoint , mlh1 , epithelial cell adhesion molecule , germline , microbiology and biotechnology , dna mismatch repair , gene , cancer , dna repair , chromosomal translocation , recombination , genetic recombination
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. Hum Mutat 32:1–8, 2011. © 2011 Wiley‐Liss, Inc.