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, RP15
Vissers, LELM15
Venkatachalam, R15
Bodmer, D15
Hoenselaar, E15
Goossens, M15
Haufe, A6
Kamping, E15
Niessen, RC10
Hogervorst, FBL7
Gille, JJP11
Redeker, B5
Tops, CMJ18
van Gijn, ME20
van den Ouweland, AMW3
Rahner, N1
Steinke, V1
Kahl, P1
HolinskiFeder, E14
Morak, M9 14
Kloor, M17
Stemmler, S2
Betz, B19
Hutter, P12
Bunyan, DJ4
Syngal, S16
Culver, JO
Graham, T13
Chan, TL8
Nagtegaal, ID15
van Krieken, JHJM15
Schackert, HK6
Hoogerbrugge, N15
van Kessel, AG15
Ligtenberg, MJL15
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
2011 Impact Factor: 5.686
2011 SCImago Journal Rankings: 0.773
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 Field
Value
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
2011 Impact Factor: 5.686
2011 SCImago Journal Rankings: 0.773
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
Author Affiliations
  1. Universität Bonn
  2. Universität Bochum
  3. Erasmus University Medical Center
  4. Salisbury District Hospital
  5. Academic Medical Centre, University of Amsterdam
  6. Dresden University Faculty of Medicine and University Hospital Carl Gustav Carus
  7. The Netherlands Cancer Institute
  8. The University of Hong Kong
  9. Center of Medical Genetics
  10. Universitair Medisch Centrum Groningen
  11. VU University Medical Center
  12. Institut Central des Hôpitaux Valaisans
  13. null
  14. Klinikum der Universität München
  15. Radboud University Nijmegen Medical Centre
  16. Brigham and Women's Hospital
  17. null
  18. Leiden University Medical Center - LUMC
  19. null
  20. University Medical Center Utrecht