title: Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1.
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.
authors.affiliation: Department of Human Genetics 849, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. m.ligtenberg@antrg.umcn.nl
authors.forename: Marjolijn J L
authors.initials: MJ
authors.lastname: Ligtenberg
authors.forename: Roland P
authors.initials: RP
authors.lastname: Kuiper
authors.forename: Tsun Leung
authors.initials: TL
authors.lastname: Chan
authors.forename: Monique
authors.initials: M
authors.lastname: Goossens
authors.forename: Konnie M
authors.initials: KM
authors.lastname: Hebeda
authors.forename: Marsha
authors.initials: M
authors.lastname: Voorendt
authors.forename: Tracy Y H
authors.initials: TY
authors.lastname: Lee
authors.forename: Danielle
authors.initials: D
authors.lastname: Bodmer
authors.forename: Eveline
authors.initials: E
authors.lastname: Hoenselaar
authors.forename: Sandra J B
authors.initials: SJ
authors.lastname: Hendriks-Cornelissen
authors.forename: Wai Yin
authors.initials: WY
authors.lastname: Tsui
authors.forename: Chi Kwan
authors.initials: CK
authors.lastname: Kong
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Ad Geurts
authors.initials: AG
authors.lastname: van Kessel
authors.forename: Siu Tsan
authors.initials: ST
authors.lastname: Yuen
authors.forename: J Han J M
authors.initials: JH
authors.lastname: van Krieken
authors.forename: Suet Yi
authors.initials: SY
authors.lastname: Leung
authors.forename: Nicoline
authors.initials: N
authors.lastname: Hoogerbrugge
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000951:Antigens, Neoplasm / Q000235:genetics*; D044466:Asian People; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002681:China; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D019175:DNA Methylation; D000071858:Epithelial Cell Adhesion Molecule; D005091:Exons / Q000235:genetics*; D005190:Family; D005260:Female; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics*; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D008969:Molecular Sequence Data; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009426:Netherlands; D016366:Open Reading Frames / Q000235:genetics; D010375:Pedigree; D011401:Promoter Regions, Genetic / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein