title: Recurrence and variability of germline EPCAM deletions in Lynch syndrome.
abstract: 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.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. r.kuiper@antrg.umcn.nl
authors.forename: Roland P
authors.initials: RP
authors.lastname: Kuiper
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.forename: Ramprasath
authors.initials: R
authors.lastname: Venkatachalam
authors.forename: Danielle
authors.initials: D
authors.lastname: Bodmer
authors.forename: Eveline
authors.initials: E
authors.lastname: Hoenselaar
authors.forename: Monique
authors.initials: M
authors.lastname: Goossens
authors.forename: Aline
authors.initials: A
authors.lastname: Haufe
authors.forename: Eveline
authors.initials: E
authors.lastname: Kamping
authors.forename: Renée C
authors.initials: RC
authors.lastname: Niessen
authors.forename: Frans B L
authors.initials: FB
authors.lastname: Hogervorst
authors.forename: Johan J P
authors.initials: JJ
authors.lastname: Gille
authors.forename: Bert
authors.initials: B
authors.lastname: Redeker
authors.forename: Carli M J
authors.initials: CM
authors.lastname: Tops
authors.forename: Marielle E
authors.initials: ME
authors.lastname: van Gijn
authors.forename: Ans M W
authors.initials: AM
authors.lastname: van den Ouweland
authors.forename: Nils
authors.initials: N
authors.lastname: Rahner
authors.forename: Verena
authors.initials: V
authors.lastname: Steinke
authors.forename: Philip
authors.initials: P
authors.lastname: Kahl
authors.forename: Elke
authors.initials: E
authors.lastname: Holinski-Feder
authors.forename: Monika
authors.initials: M
authors.lastname: Morak
authors.forename: Matthias
authors.initials: M
authors.lastname: Kloor
authors.forename: Susanne
authors.initials: S
authors.lastname: Stemmler
authors.forename: Beate
authors.initials: B
authors.lastname: Betz
authors.forename: Pierre
authors.initials: P
authors.lastname: Hutter
authors.forename: David J
authors.initials: DJ
authors.lastname: Bunyan
authors.forename: Sapna
authors.initials: S
authors.lastname: Syngal
authors.forename: Julie O
authors.initials: JO
authors.lastname: Culver
authors.forename: Tracy
authors.initials: T
authors.lastname: Graham
authors.forename: Tsun L
authors.initials: TL
authors.lastname: Chan
authors.forename: Iris D
authors.initials: ID
authors.lastname: Nagtegaal
authors.forename: J Han J M
authors.initials: JH
authors.lastname: van Krieken
authors.forename: Hans K
authors.initials: HK
authors.lastname: Schackert
authors.forename: Nicoline
authors.initials: N
authors.lastname: Hoogerbrugge
authors.forename: Ad Geurts
authors.initials: AG
authors.lastname: van Kessel
authors.forename: Marjolijn J L
authors.initials: MJ
authors.lastname: Ligtenberg
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D019175:DNA Methylation; D000071858:Epithelial Cell Adhesion Molecule; D014644:Genetic Variation; D018095:Germ-Line Mutation / Q000235:genetics*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D009426:Netherlands; D011401:Promoter Regions, Genetic; D012008:Recurrence; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D051718:MutS Homolog 2 Protein