{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T20:44:17Z","timestamp":1789937057674,"version":"4.0.1"},"reference-count":42,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2014,9,30]],"date-time":"2014-09-30T00:00:00Z","timestamp":1412035200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003061","name":"Erasmus Medisch Centrum","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003061","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2014,12]]},"abstract":"Abstract<\/jats:title>Lynch syndrome (LS<\/jats:styled-content>) is caused by germline mutations in mismatch repair (MMR<\/jats:styled-content>) genes, resulting in microsatellite\u2010unstable tumours. Approximately 35% of suspected LS<\/jats:styled-content> (sLS<\/jats:styled-content>) patients test negative for germline MMR<\/jats:styled-content> gene mutations, hampering conclusive LS<\/jats:styled-content> diagnosis. The aim of this study was to investigate somatic MMR<\/jats:styled-content> gene aberrations in microsatellite\u2010unstable colorectal and endometrial cancers of sLS<\/jats:styled-content> patients negative for germline MMR<\/jats:styled-content> gene mutations. Suspected LS<\/jats:styled-content> cases were selected from a retrospective Clinical Genetics Department diagnostic cohort and from a prospective multicentre population\u2010based study on LS<\/jats:styled-content> in The Netherlands. In total, microsatellite\u2010unstable tumours of 40 sLS<\/jats:styled-content> patients (male\/female 20\/20, median age 57 years) were screened for somatic MMR<\/jats:styled-content> gene mutations by next\u2010generation sequencing. In addition, loss of heterozygosity (LOH<\/jats:styled-content>) of the affected MMR<\/jats:styled-content> genes in these tumours as well as in 68 LS<\/jats:styled-content>\u2010associated tumours and 27 microsatellite\u2010unstable tumours with MLH1<\/jats:styled-content><\/jats:italic> promoter hypermethylation was studied. Of the sLS<\/jats:styled-content> cases, 5\/40 (13%) tumours had two pathogenic somatic mutations and 16\/40 (40%) tumours had a (likely) pathogenic mutation and LOH<\/jats:styled-content>. Overall, LOH<\/jats:styled-content> of the affected MMR<\/jats:styled-content> gene locus was observed in 24\/39 (62%) tumours with informative LOH<\/jats:styled-content> markers. Of the LS<\/jats:styled-content> cases and the tumours with MLH1<\/jats:styled-content><\/jats:italic> promoter hypermethylation, 39\/61 (64%) and 2\/21 (10%) tumours, respectively, demonstrated LOH<\/jats:styled-content>. Half of microsatellite\u2010unstable tumours of sLS<\/jats:styled-content> patients without germline MMR<\/jats:styled-content> gene mutations had two (likely) deleterious somatic MMR<\/jats:styled-content> gene aberrations, indicating their sporadic origin. Therefore, we advocate adding somatic mutation and LOH<\/jats:styled-content> analysis of the MMR<\/jats:styled-content> genes to the molecular diagnostic workflow of LS<\/jats:styled-content>. Copyright \u00a9 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd<\/jats:p>","DOI":"10.1002\/path.4419","type":"journal-article","created":{"date-parts":[[2014,10,15]],"date-time":"2014-10-15T06:35:07Z","timestamp":1413354907000},"page":"548-559","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":143,"title":["Somatic aberrations of mismatch repair genes as a cause of microsatellite\u2010unstable cancers"],"prefix":"10.1002","volume":"234","author":[{"given":"Willemina RR","family":"Geurts\u2010Giele","sequence":"first","affiliation":[{"name":"Department of Pathology Erasmus MC Cancer Institute, University Medical Centre Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine HM","family":"Leenen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Erasmus MC, University Medical Centre Rotterdam The 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