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

File Download Links for fulltext
(May Require Subscription)
Supplementary
  • Basic View
  • Metadata View
  • XML View
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
2011 Impact Factor: 35.532
2011 SCImago Journal Rankings: 8.923
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
Molecular characterisation of the serrated neoplasia pathway and its role in the development of colorectal cancer with mismatch repair deficiency
DC Field
Value
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.grantMolecular characterisation of the serrated neoplasia pathway and its role in the development of colorectal cancer with mismatch repair deficiency
dc.description.grantMolecular characterisation of the serrated neoplasia pathway and its role in the development of colorectal cancer with mismatch repair deficiency
dc.description.grantcode29673
dc.description.grantcode28039
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.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
2011 Impact Factor: 35.532
2011 SCImago Journal Rankings: 8.923
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.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
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