Recurrence and variability of germline EPCAM deletions in Lynch syndrome

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...

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Published in:	Human mutation Vol. 32; no. 4; pp. 407 - 414
Main Authors:	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, Holinski-Feder, 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.
Format:	Journal Article
Language:	English
Published:	Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-04-2011 Hindawi Limited Wiley
Subjects:	Alu-mediated recombination Antigens, Neoplasm - genetics Antigens, Neoplasm - metabolism Base Sequence Cell Adhesion Molecules - genetics Cell Adhesion Molecules - metabolism Colorectal Neoplasms, Hereditary Nonpolyposis - genetics DNA Methylation EPCAM Epithelial Cell Adhesion Molecule Genetic Variation Germ-Line Mutation - genetics Lynch syndrome Models, Genetic Molecular Sequence Data MutS Homolog 2 Protein - genetics MutS Homolog 2 Protein - metabolism NAHR Netherlands Promoter Regions, Genetic Recurrence Sequence Deletion - genetics TACSTD1 Life Sciences
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Summary:	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.
Bibliography:	The Deutsche Krebshilfe - No. Familial Colorectal Cancer 70-3032 ark:/67375/WNG-C62BCGTW-R istex:1EA81C06B524687B0DCC25F4C1600E26260A9B58 Communicated by Albert de la Chapelle The Dutch Cancer Society - No. 2009-4335 (to M.J.L., R.P.K., and N.H.) The Netherlands Organization for Health Research and Development - No. ZonMW 917-10-358 (to R.P.K.); No. ZonMW 916-86-016 (to L.E.L.M.V.) ArticleID:HUMU21446 The Sacha Swarttouw-Hijmans Foundation (to N.H. and M.J.L.) ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	1059-7794 1098-1004 1098-1004
DOI:	10.1002/humu.21446