{"entity":{"id":"paper-ligtenberg-epcam-deletion-msh2-silencing-nat-genet-2009","kind":"paper","name":"Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1","aka":[],"tldr":"Some families with inherited bowel cancer have no mutation in any repair gene. The fault is in the neighbouring gene: losing its end makes it run on into the repair gene and chemically silence it, but only in the tissues where the neighbour is switched on.","summary":"Patients from Dutch and Chinese families with MSH2-deficient tumours were found to carry heterozygous germline deletions of the last exons of TACSTD1 (EPCAM), the gene directly upstream of MSH2. Because of these deletions, transcription of TACSTD1 extends into MSH2. The MSH2 promoter in cis with the deletion was methylated in EpCAM-positive but not in EpCAM-negative normal tissues, showing a correlation between activity of the mutated TACSTD1 allele and epigenetic inactivation of the corresponding MSH2 allele. The authors proposed gene silencing by transcriptional read-through of a neighbouring gene as a general mutational mechanism, producing generalised or mosaic epigenetic inactivation depending on the neighbour's expression pattern.","asOf":"2026-09-24","links":[{"label":"Ligtenberg et al., Nat Genet 2009: EPCAM (TACSTD1) 3' deletions silence MSH2 in Lynch syndrome","url":"https://doi.org/10.1038/ng.283"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/19098912/"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":["germline-testing"],"targets":["msh2","epcam","mmr"],"drugs":[],"companies":[],"institutions":["radboudumc"],"pathways":["mismatch-repair-msi","epigenetic-reprogramming"],"terms":["lynch-syndrome","hereditary-cancer-syndromes","germline-vs-somatic"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature-genetics"],"dependsOn":[],"notes":[],"journal":"Nature Genetics","year":2009,"doi":"10.1038/ng.283","pmid":"19098912","authors":"Ligtenberg MJ, Kuiper RP, Chan TL, et al.","paperType":"basic","findings":["3' EPCAM (TACSTD1) deletions cause tissue-specific MSH2 promoter methylation in cis.","A new class of Lynch syndrome with no mismatch repair gene mutation."],"whatItMeans":"EPCAM deletion testing is now part of Lynch syndrome panels, and it explains the MSH2-deficient tumours in families where sequencing of the four repair genes comes back clean.","caveats":["Rare: a small percentage of Lynch syndrome.","Copy-number analysis, not sequencing, is needed to find it."],"changedPractice":true},"route":"/key-papers/paper-ligtenberg-epcam-deletion-msh2-silencing-nat-genet-2009/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"}],"technology":[{"id":"germline-testing","kind":"technology","name":"Germline (hereditary) testing","route":"/technologies/germline-testing/"}],"target":[{"id":"epcam","kind":"target","name":"EpCAM","route":"/targets/epcam/"},{"id":"mmr","kind":"target","name":"Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)","route":"/targets/mmr/"},{"id":"msh2","kind":"target","name":"MSH2","route":"/targets/msh2/"}],"institution":[{"id":"radboudumc","kind":"institution","name":"Radboudumc Centre for Oncology","route":"/institutions/radboudumc/"}],"pathway":[{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"mismatch-repair-msi","kind":"pathway","name":"Mismatch repair & microsatellite instability","route":"/pathways/mismatch-repair-msi/"}],"term":[{"id":"germline-vs-somatic","kind":"term","name":"Germline vs somatic mutations","route":"/terms/germline-vs-somatic/"},{"id":"hereditary-cancer-syndromes","kind":"term","name":"Hereditary cancer syndromes","route":"/terms/hereditary-cancer-syndromes/"},{"id":"lynch-syndrome","kind":"term","name":"Lynch syndrome","route":"/terms/lynch-syndrome/"}],"journal":[{"id":"nature-genetics","kind":"journal","name":"Nature Genetics","route":"/journals/nature-genetics/"}]}}