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Article: Recurrence and variability of germline EPCAM deletions in Lynch syndrome

TitleRecurrence and variability of germline EPCAM deletions in Lynch syndrome
Authors
Issue Date2011
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/38515
Citation
Human Mutation, 2011, v. 32 n. 4, p. 407-414 How to Cite?
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. © 2011 Wiley-Liss, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/139940
ISSN
2013 Impact Factor: 5.050
ISI Accession Number ID
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.

References

 

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
DC FieldValueLanguage
dc.contributor.authorKuiper, RPen_HK
dc.contributor.authorVissers, LELMen_HK
dc.contributor.authorVenkatachalam, Ren_HK
dc.contributor.authorBodmer, Den_HK
dc.contributor.authorHoenselaar, Een_HK
dc.contributor.authorGoossens, Men_HK
dc.contributor.authorHaufe, Aen_HK
dc.contributor.authorKamping, Een_HK
dc.contributor.authorNiessen, RCen_HK
dc.contributor.authorHogervorst, FBLen_HK
dc.contributor.authorGille, JJPen_HK
dc.contributor.authorRedeker, Ben_HK
dc.contributor.authorTops, CMJen_HK
dc.contributor.authorvan Gijn, MEen_HK
dc.contributor.authorvan den Ouweland, AMWen_HK
dc.contributor.authorRahner, Nen_HK
dc.contributor.authorSteinke, Ven_HK
dc.contributor.authorKahl, Pen_HK
dc.contributor.authorHolinskiFeder, Een_HK
dc.contributor.authorMorak, Men_HK
dc.contributor.authorKloor, Men_HK
dc.contributor.authorStemmler, Sen_HK
dc.contributor.authorBetz, Ben_HK
dc.contributor.authorHutter, Pen_HK
dc.contributor.authorBunyan, DJen_HK
dc.contributor.authorSyngal, Sen_HK
dc.contributor.authorCulver, JOen_HK
dc.contributor.authorGraham, Ten_HK
dc.contributor.authorChan, TLen_HK
dc.contributor.authorNagtegaal, IDen_HK
dc.contributor.authorvan Krieken, JHJMen_HK
dc.contributor.authorSchackert, HKen_HK
dc.contributor.authorHoogerbrugge, Nen_HK
dc.contributor.authorvan Kessel, AGen_HK
dc.contributor.authorLigtenberg, MJLen_HK
dc.date.accessioned2011-09-23T06:02:11Z-
dc.date.available2011-09-23T06:02:11Z-
dc.date.issued2011en_HK
dc.identifier.citationHuman Mutation, 2011, v. 32 n. 4, p. 407-414en_HK
dc.identifier.issn1059-7794en_HK
dc.identifier.urihttp://hdl.handle.net/10722/139940-
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.en_HK
dc.languageengen_US
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/38515en_HK
dc.relation.ispartofHuman Mutationen_HK
dc.subject.meshAntigens, Neoplasm - genetics - metabolismen_HK
dc.subject.meshBase Sequenceen_HK
dc.subject.meshCell Adhesion Molecules - genetics - metabolismen_HK
dc.subject.meshColorectal Neoplasms, Hereditary Nonpolyposis - geneticsen_HK
dc.subject.meshDNA Methylationen_HK
dc.subject.meshGenetic Variationen_HK
dc.subject.meshGerm-Line Mutation - geneticsen_HK
dc.subject.meshModels, Geneticen_HK
dc.subject.meshMolecular Sequence Dataen_HK
dc.subject.meshMutS Homolog 2 Protein - genetics - metabolismen_HK
dc.subject.meshNetherlandsen_HK
dc.subject.meshPromoter Regions, Geneticen_HK
dc.subject.meshRecurrenceen_HK
dc.subject.meshSequence Deletion - geneticsen_HK
dc.titleRecurrence and variability of germline EPCAM deletions in Lynch syndromeen_HK
dc.typeArticleen_HK
dc.identifier.emailChan, TL:tlchan@hku.hken_HK
dc.identifier.authorityChan, TL=rp00418en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/humu.21446en_HK
dc.identifier.pmid21309036en_HK
dc.identifier.scopuseid_2-s2.0-79952754996en_HK
dc.identifier.hkuros192590en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79952754996&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume32en_HK
dc.identifier.issue4en_HK
dc.identifier.spage407en_HK
dc.identifier.epage414en_HK
dc.identifier.isiWOS:000288464100013-
dc.publisher.placeUnited Statesen_HK

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