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Article: Recurrence and variability of germline EPCAM deletions in Lynch syndrome
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TitleRecurrence and variability of germline EPCAM deletions in Lynch syndrome
 
AuthorsKuiper, RP14
Vissers, LELM14
Venkatachalam, R14
Bodmer, D14
Hoenselaar, E14
Goossens, M14
Haufe, A5
Kamping, E14
Niessen, RC10
Hogervorst, FBL7
Gille, JJP12
Redeker, B4
Tops, CMJ18
van Gijn, ME20
van den Ouweland, AMW6
Rahner, N2
Steinke, V2
Kahl, P2
HolinskiFeder, E16
Morak, M9 16
Kloor, M17
Stemmler, S1
Betz, B19
Hutter, P11
Bunyan, DJ3
Syngal, S15
Culver, JO
Graham, T13
Chan, TL8
Nagtegaal, ID14
van Krieken, JHJM14
Schackert, HK5
Hoogerbrugge, N14
van Kessel, AG14
Ligtenberg, MJL14
 
Issue Date2011
 
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/38515
 
CitationHuman Mutation, 2011, v. 32 n. 4, p. 407-414 [How to Cite?]
DOI: http://dx.doi.org/10.1002/humu.21446
 
AbstractRecently, 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. © 2011 Wiley-Liss, Inc.
 
ISSN1059-7794
2013 Impact Factor: 5.050
 
DOIhttp://dx.doi.org/10.1002/humu.21446
 
ISI Accession Number IDWOS:000288464100013
Funding AgencyGrant Number
The Dutch Cancer Society20094335
The Netherlands Organization for Health Research and DevelopmentZonMW 917-10-358
ZonMW 916-86-016
The Sacha Swarttouw-Hijmans Foundation
The Deutsche KrebshilfeFamilial Colorectal Cancer 70-3032
Funding Information:

Contract grant sponsor: The Dutch Cancer Society; Contract grant number: 20094335 (to M.J.L., R.P.K., and N.H.); Contract grant sponsor: The Netherlands Organization for Health Research and Development; Contract grant numbers: ZonMW 917-10-358 (to R.P.K.); ZonMW 916-86-016 (to L.E.L.M.V.); Contract grant sponsors: The Sacha Swarttouw-Hijmans Foundation (to N.H. and M.J.L.); The Deutsche Krebshilfe; Contract grant number: Familial Colorectal Cancer 70-3032.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorKuiper, RP
 
dc.contributor.authorVissers, LELM
 
dc.contributor.authorVenkatachalam, R
 
dc.contributor.authorBodmer, D
 
dc.contributor.authorHoenselaar, E
 
dc.contributor.authorGoossens, M
 
dc.contributor.authorHaufe, A
 
dc.contributor.authorKamping, E
 
dc.contributor.authorNiessen, RC
 
dc.contributor.authorHogervorst, FBL
 
dc.contributor.authorGille, JJP
 
dc.contributor.authorRedeker, B
 
dc.contributor.authorTops, CMJ
 
dc.contributor.authorvan Gijn, ME
 
dc.contributor.authorvan den Ouweland, AMW
 
dc.contributor.authorRahner, N
 
dc.contributor.authorSteinke, V
 
dc.contributor.authorKahl, P
 
dc.contributor.authorHolinskiFeder, E
 
dc.contributor.authorMorak, M
 
dc.contributor.authorKloor, M
 
dc.contributor.authorStemmler, S
 
dc.contributor.authorBetz, B
 
dc.contributor.authorHutter, P
 
dc.contributor.authorBunyan, DJ
 
dc.contributor.authorSyngal, S
 
dc.contributor.authorCulver, JO
 
dc.contributor.authorGraham, T
 
dc.contributor.authorChan, TL
 
dc.contributor.authorNagtegaal, ID
 
dc.contributor.authorvan Krieken, JHJM
 
dc.contributor.authorSchackert, HK
 
dc.contributor.authorHoogerbrugge, N
 
dc.contributor.authorvan Kessel, AG
 
dc.contributor.authorLigtenberg, MJL
 
dc.date.accessioned2011-09-23T06:02:11Z
 
dc.date.available2011-09-23T06:02:11Z
 
dc.date.issued2011
 
dc.description.abstractRecently, 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. © 2011 Wiley-Liss, Inc.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationHuman Mutation, 2011, v. 32 n. 4, p. 407-414 [How to Cite?]
DOI: http://dx.doi.org/10.1002/humu.21446
 
dc.identifier.doihttp://dx.doi.org/10.1002/humu.21446
 
dc.identifier.epage414
 
dc.identifier.hkuros192590
 
dc.identifier.isiWOS:000288464100013
Funding AgencyGrant Number
The Dutch Cancer Society20094335
The Netherlands Organization for Health Research and DevelopmentZonMW 917-10-358
ZonMW 916-86-016
The Sacha Swarttouw-Hijmans Foundation
The Deutsche KrebshilfeFamilial Colorectal Cancer 70-3032
Funding Information:

Contract grant sponsor: The Dutch Cancer Society; Contract grant number: 20094335 (to M.J.L., R.P.K., and N.H.); Contract grant sponsor: The Netherlands Organization for Health Research and Development; Contract grant numbers: ZonMW 917-10-358 (to R.P.K.); ZonMW 916-86-016 (to L.E.L.M.V.); Contract grant sponsors: The Sacha Swarttouw-Hijmans Foundation (to N.H. and M.J.L.); The Deutsche Krebshilfe; Contract grant number: Familial Colorectal Cancer 70-3032.

 
dc.identifier.issn1059-7794
2013 Impact Factor: 5.050
 
dc.identifier.issue4
 
dc.identifier.pmid21309036
 
dc.identifier.scopuseid_2-s2.0-79952754996
 
dc.identifier.spage407
 
dc.identifier.urihttp://hdl.handle.net/10722/139940
 
dc.identifier.volume32
 
dc.languageeng
 
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/38515
 
dc.publisher.placeUnited States
 
dc.relation.ispartofHuman Mutation
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAntigens, Neoplasm - genetics - metabolism
 
dc.subject.meshBase Sequence
 
dc.subject.meshCell Adhesion Molecules - genetics - metabolism
 
dc.subject.meshColorectal Neoplasms, Hereditary Nonpolyposis - genetics
 
dc.subject.meshDNA Methylation
 
dc.subject.meshGenetic Variation
 
dc.subject.meshGerm-Line Mutation - genetics
 
dc.subject.meshModels, Genetic
 
dc.subject.meshMolecular Sequence Data
 
dc.subject.meshMutS Homolog 2 Protein - genetics - metabolism
 
dc.subject.meshNetherlands
 
dc.subject.meshPromoter Regions, Genetic
 
dc.subject.meshRecurrence
 
dc.subject.meshSequence Deletion - genetics
 
dc.titleRecurrence and variability of germline EPCAM deletions in Lynch syndrome
 
dc.typeArticle
 
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Author Affiliations
  1. Universität Bochum
  2. Universität Bonn
  3. Salisbury District Hospital
  4. Academic Medical Centre, University of Amsterdam
  5. Dresden University Faculty of Medicine and University Hospital Carl Gustav Carus
  6. Erasmus University Medical Center
  7. The Netherlands Cancer Institute
  8. The University of Hong Kong
  9. Center of Medical Genetics
  10. Universitair Medisch Centrum Groningen
  11. Institut Central des Hôpitaux Valaisans
  12. VU University Medical Center
  13. null
  14. Radboud University Nijmegen Medical Centre
  15. Brigham and Women's Hospital
  16. Klinikum der Universität München
  17. null
  18. Leiden University Medical Center - LUMC
  19. null
  20. University Medical Center Utrecht