Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1.
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.
Ligtenberg
Marjolijn J L
MJ
Department of Human Genetics 849, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. m.ligtenberg@antrg.umcn.nl
Kuiper
Roland P
RP
Chan
Tsun Leung
TL
Goossens
Monique
M
Hebeda
Konnie M
KM
Voorendt
Marsha
M
Lee
Tracy Y H
TY
Bodmer
Danielle
D
Hoenselaar
Eveline
E
Hendriks-Cornelissen
Sandra J B
SJ
Tsui
Wai Yin
WY
Kong
Chi Kwan
CK
Brunner
Han G
HG
van Kessel
Ad Geurts
AG
Yuen
Siu Tsan
ST
van Krieken
J Han J M
JH
Leung
Suet Yi
SY
Hoogerbrugge
Nicoline
N
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
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