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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
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TitleHeritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1
 
AuthorsLigtenberg, MJL4
Kuiper, RP4
Chan, TL2 3
Goossens, M4
Hebeda, KM4
Voorendt, M4
Lee, TYH2
Bodmer, D4
Hoenselaar, E4
HendriksCornelissen, SJB4
Tsui, WY2
Kong, CK1
Brunner, HG4
Van Kessel, AG4
Yuen, ST2 3
Van Krieken, JHJM4
Leung, SY2 3
Hoogerbrugge, N4
 
Issue Date2009
 
PublisherNature Publishing Group. The Journal's web site is located at http://www.genetics.nature.com
 
CitationNature Genetics, 2009, v. 41 n. 1, p. 112-117 [How to Cite?]
DOI: http://dx.doi.org/10.1038/ng.283
 
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.
 
ISSN1061-4036
2013 Impact Factor: 29.648
2013 SCImago Journal Rankings: 24.052
 
DOIhttp://dx.doi.org/10.1038/ng.283
 
ISI Accession Number IDWOS:000262085300025
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.

 
ReferencesReferences in Scopus
 
GrantsMolecular characterisation of the serrated neoplasia pathway and its role in the development of colorectal cancer with mismatch repair deficiency
 
DC FieldValue
dc.contributor.authorLigtenberg, MJL
 
dc.contributor.authorKuiper, RP
 
dc.contributor.authorChan, TL
 
dc.contributor.authorGoossens, M
 
dc.contributor.authorHebeda, KM
 
dc.contributor.authorVoorendt, M
 
dc.contributor.authorLee, TYH
 
dc.contributor.authorBodmer, D
 
dc.contributor.authorHoenselaar, E
 
dc.contributor.authorHendriksCornelissen, SJB
 
dc.contributor.authorTsui, WY
 
dc.contributor.authorKong, CK
 
dc.contributor.authorBrunner, HG
 
dc.contributor.authorVan Kessel, AG
 
dc.contributor.authorYuen, ST
 
dc.contributor.authorVan Krieken, JHJM
 
dc.contributor.authorLeung, SY
 
dc.contributor.authorHoogerbrugge, N
 
dc.date.accessioned2012-05-29T06:13:59Z
 
dc.date.available2012-05-29T06:13:59Z
 
dc.date.issued2009
 
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.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationNature Genetics, 2009, v. 41 n. 1, p. 112-117 [How to Cite?]
DOI: http://dx.doi.org/10.1038/ng.283
 
dc.identifier.citeulike3832920
 
dc.identifier.doihttp://dx.doi.org/10.1038/ng.283
 
dc.identifier.eissn1546-1718
 
dc.identifier.epage117
 
dc.identifier.hkuros159584
 
dc.identifier.isiWOS:000262085300025
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.

 
dc.identifier.issn1061-4036
2013 Impact Factor: 29.648
2013 SCImago Journal Rankings: 24.052
 
dc.identifier.issue1
 
dc.identifier.pmid19098912
 
dc.identifier.scopuseid_2-s2.0-58149144567
 
dc.identifier.spage112
 
dc.identifier.urihttp://hdl.handle.net/10722/148596
 
dc.identifier.volume41
 
dc.languageeng
 
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.genetics.nature.com
 
dc.publisher.placeUnited States
 
dc.relation.ispartofNature Genetics
 
dc.relation.projectMolecular characterisation of the serrated neoplasia pathway and its role in the development of colorectal cancer with mismatch repair deficiency
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAdolescent
 
dc.subject.meshAdult
 
dc.subject.meshAlleles
 
dc.subject.meshAntigens, Neoplasm - Genetics
 
dc.subject.meshAsian Continental Ancestry Group
 
dc.subject.meshBase Sequence
 
dc.subject.meshCell Adhesion Molecules - Genetics
 
dc.subject.meshChina
 
dc.subject.meshColorectal Neoplasms, Hereditary Nonpolyposis - Genetics
 
dc.subject.meshDna Methylation
 
dc.subject.meshEuropean Continental Ancestry Group - Genetics
 
dc.subject.meshExons - Genetics
 
dc.subject.meshFamily
 
dc.subject.meshFemale
 
dc.subject.meshHumans
 
dc.subject.meshInheritance Patterns - Genetics
 
dc.subject.meshMale
 
dc.subject.meshMicrosatellite Instability
 
dc.subject.meshMiddle Aged
 
dc.subject.meshMolecular Sequence Data
 
dc.subject.meshMuts Homolog 2 Protein - Genetics
 
dc.subject.meshNetherlands
 
dc.subject.meshOpen Reading Frames - Genetics
 
dc.subject.meshPedigree
 
dc.subject.meshPromoter Regions, Genetic - Genetics
 
dc.subject.meshSequence Deletion - Genetics
 
dc.titleHeritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1
 
dc.typeArticle
 
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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