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Article: Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1

TitleHeritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1
Authors
Issue Date2009
PublisherNature Publishing Group. The Journal's web site is located at http://www.genetics.nature.com
Citation
Nature Genetics, 2009, v. 41 n. 1, p. 112-117 How to Cite?
Abstract
Lynch syndrome patients are susceptible to colorectal and endometrial cancers owing to inactivating germline mutations in mismatch repair genes, including MSH2 (ref. 1). Here we describe patients from Dutch and Chinese families with MSH2-deficient tumors carrying heterozygous germline deletions of the last exons of TACSTD1, a gene directly upstream of MSH2 encoding Ep-CAM. Due to these deletions, transcription of TACSTD1 extends into MSH2. The MSH2 promoter in cis with the deletion is methylated in Ep-CAM positive but not in Ep-CAM negative normal tissues, thus revealing a correlation between activity of the mutated TACSTD1 allele and epigenetic inactivation of the corresponding MSH2 allele. Gene silencing by transcriptional read-through of a neighboring gene in either sense, as demonstrated here, or antisense direction, could represent a general mutational mechanism. Depending on the expression pattern of the neighboring gene that lacks its normal polyadenylation signal, this may cause either generalized or mosaic patterns of epigenetic inactivation. © 2009 Nature America, Inc. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/148596
ISSN
2013 Impact Factor: 29.648
2013 SCImago Journal Rankings: 24.052
ISI Accession Number ID
Funding AgencyGrant Number
Dutch Cancer Society
Research Grants Council of the Hong Kong Special Administrative RegionGRF HKU 7614/08M
HKU 7622/05M
Hong Kong Cancer Fund
Michael and Betty Kadoorie Cancer Genetics Research Programme
Funding Information:

We thank S. Wezenberg, M. Schliekelmann, E. Kamping, M. Steehouwer, R. Willems, A. S. Y. Chan, A. K. W. Chan, J. K. Y. Lau and C. Li for technical assistance, Diederik de Bruijn for advice and support, and clinicians in Hong Kong Hospital Authority for clinical care. This work was supported by research grants from the Dutch Cancer Society, the Research Grants Council of the Hong Kong Special Administrative Region (GRF HKU 7614/08M and HKU 7622/05M), the Hong Kong Cancer Fund and the Michael and Betty Kadoorie Cancer Genetics Research Programme.

References
Grants

 

Author Affiliations
  1. Yan Chai Hospital - Hong Kong
  2. The University of Hong Kong
  3. St. Paul's Hospital Hong Kong
  4. Radboud University Nijmegen Medical Centre
DC FieldValueLanguage
dc.contributor.authorLigtenberg, MJLen_US
dc.contributor.authorKuiper, RPen_US
dc.contributor.authorChan, TLen_US
dc.contributor.authorGoossens, Men_US
dc.contributor.authorHebeda, KMen_US
dc.contributor.authorVoorendt, Men_US
dc.contributor.authorLee, TYHen_US
dc.contributor.authorBodmer, Den_US
dc.contributor.authorHoenselaar, Een_US
dc.contributor.authorHendriksCornelissen, SJBen_US
dc.contributor.authorTsui, WYen_US
dc.contributor.authorKong, CKen_US
dc.contributor.authorBrunner, HGen_US
dc.contributor.authorVan Kessel, AGen_US
dc.contributor.authorYuen, STen_US
dc.contributor.authorVan Krieken, JHJMen_US
dc.contributor.authorLeung, SYen_US
dc.contributor.authorHoogerbrugge, Nen_US
dc.date.accessioned2012-05-29T06:13:59Z-
dc.date.available2012-05-29T06:13:59Z-
dc.date.issued2009en_US
dc.identifier.citationNature Genetics, 2009, v. 41 n. 1, p. 112-117en_US
dc.identifier.issn1061-4036en_US
dc.identifier.urihttp://hdl.handle.net/10722/148596-
dc.description.abstractLynch syndrome patients are susceptible to colorectal and endometrial cancers owing to inactivating germline mutations in mismatch repair genes, including MSH2 (ref. 1). Here we describe patients from Dutch and Chinese families with MSH2-deficient tumors carrying heterozygous germline deletions of the last exons of TACSTD1, a gene directly upstream of MSH2 encoding Ep-CAM. Due to these deletions, transcription of TACSTD1 extends into MSH2. The MSH2 promoter in cis with the deletion is methylated in Ep-CAM positive but not in Ep-CAM negative normal tissues, thus revealing a correlation between activity of the mutated TACSTD1 allele and epigenetic inactivation of the corresponding MSH2 allele. Gene silencing by transcriptional read-through of a neighboring gene in either sense, as demonstrated here, or antisense direction, could represent a general mutational mechanism. Depending on the expression pattern of the neighboring gene that lacks its normal polyadenylation signal, this may cause either generalized or mosaic patterns of epigenetic inactivation. © 2009 Nature America, Inc. All rights reserved.en_US
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.genetics.nature.comen_US
dc.relation.ispartofNature Geneticsen_US
dc.subject.meshAdolescenten_US
dc.subject.meshAdulten_US
dc.subject.meshAllelesen_US
dc.subject.meshAntigens, Neoplasm - Geneticsen_US
dc.subject.meshAsian Continental Ancestry Groupen_US
dc.subject.meshBase Sequenceen_US
dc.subject.meshCell Adhesion Molecules - Geneticsen_US
dc.subject.meshChinaen_US
dc.subject.meshColorectal Neoplasms, Hereditary Nonpolyposis - Geneticsen_US
dc.subject.meshDna Methylationen_US
dc.subject.meshEuropean Continental Ancestry Group - Geneticsen_US
dc.subject.meshExons - Geneticsen_US
dc.subject.meshFamilyen_US
dc.subject.meshFemaleen_US
dc.subject.meshHumansen_US
dc.subject.meshInheritance Patterns - Geneticsen_US
dc.subject.meshMaleen_US
dc.subject.meshMicrosatellite Instabilityen_US
dc.subject.meshMiddle Ageden_US
dc.subject.meshMolecular Sequence Dataen_US
dc.subject.meshMuts Homolog 2 Protein - Geneticsen_US
dc.subject.meshNetherlandsen_US
dc.subject.meshOpen Reading Frames - Geneticsen_US
dc.subject.meshPedigreeen_US
dc.subject.meshPromoter Regions, Genetic - Geneticsen_US
dc.subject.meshSequence Deletion - Geneticsen_US
dc.titleHeritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1en_US
dc.typeArticleen_US
dc.identifier.emailChan, TL:tlchan@hku.hken_US
dc.identifier.emailLeung, SY:suetyi@hkucc.hku.hken_US
dc.identifier.authorityChan, TL=rp00418en_US
dc.identifier.authorityLeung, SY=rp00359en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1038/ng.283en_US
dc.identifier.pmid19098912en_US
dc.identifier.scopuseid_2-s2.0-58149144567en_US
dc.identifier.hkuros159584-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-58149144567&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume41en_US
dc.identifier.issue1en_US
dc.identifier.spage112en_US
dc.identifier.epage117en_US
dc.identifier.eissn1546-1718-
dc.identifier.isiWOS:000262085300025-
dc.publisher.placeUnited Statesen_US
dc.relation.projectMolecular characterisation of the serrated neoplasia pathway and its role in the development of colorectal cancer with mismatch repair deficiency-
dc.identifier.citeulike3832920-

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