{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T12:05:53Z","timestamp":1791115553176,"version":"4.1.0"},"reference-count":39,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2010,4,27]],"date-time":"2010-04-27T00:00:00Z","timestamp":1272326400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2011,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Lynch syndrome is an autosomal dominant cancer predisposition syndrome classically caused by germline mutations of the mismatch repair genes, <jats:italic>MLH1<\/jats:italic>, <jats:italic>MSH2<\/jats:italic>, <jats:italic>MSH6<\/jats:italic> and <jats:italic>PMS2<\/jats:italic>. Constitutional epimutations of the <jats:italic>MLH1<\/jats:italic> gene, characterized by soma\u2010wide methylation of a single allele of the promoter and allelic transcriptional silencing, have been identified in a subset of Lynch syndrome cases lacking a sequence mutation in <jats:italic>MLH1<\/jats:italic>. We report two individuals with no family history of colorectal cancer who developed that disease at age 18 and 20 years. In both cases, cancer had arisen because of the <jats:italic>de novo<\/jats:italic> occurrence of a constitutional <jats:italic>MLH1<\/jats:italic> epimutation and somatic loss\u2010of\u2010heterozygosity of the functional allele in the tumors. We show for the first time that the epimutation in one case arose on the paternally inherited allele. Analysis of 13 tumors from seven individuals with constitutional <jats:italic>MLH1<\/jats:italic> epimutations showed eight tumors had lost the second <jats:italic>MLH1<\/jats:italic> allele, two tumors had a novel pathogenic missense mutation and three had retained heterozygosity. Only 1 of 12 tumors demonstrated the BRAF V600E mutation and 3 of 11 tumors harbored a mutation in <jats:italic>KRAS<\/jats:italic>. The finding that epimutations can originate on the paternal allele provides important new insights into the mechanism of origin of epimutations. It is clear that the second hit in <jats:italic>MLH1<\/jats:italic> epimutation\u2010associated tumors typically has a genetic not epigenetic basis. Individuals with mismatch repair\u2013deficient cancers without the BRAF V600E mutation are candidates for germline screening for sequence or methylation changes in <jats:italic>MLH1<\/jats:italic>.<\/jats:p>","DOI":"10.1002\/ijc.25422","type":"journal-article","created":{"date-parts":[[2010,4,28]],"date-time":"2010-04-28T19:08:40Z","timestamp":1272481720000},"page":"869-878","source":"Crossref","is-referenced-by-count":78,"title":["<i>De novo<\/i> constitutional <i>MLH1<\/i> epimutations confer early\u2010onset colorectal cancer in two new sporadic Lynch syndrome cases, with derivation of the epimutation on the paternal allele in one"],"prefix":"10.1002","volume":"128","author":[{"given":"Ajay","family":"Goel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thuy\u2010Phuong","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hon\u2010Chiu E.","family":"Leung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Nagasaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Rhees","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Hotchkiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mildred","family":"Arnold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia","family":"Banerji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoru","family":"Koi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chau\u2010To","family":"Kwok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Packham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Lipton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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