{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:56:30Z","timestamp":1790693790088,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2018,1,17]],"date-time":"2018-01-17T00:00:00Z","timestamp":1516147200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BPD\/113014\/2015"],"award-info":[{"award-number":["SFRH\/BPD\/113014\/2015"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2018,2]]},"abstract":"Abstract<\/jats:title>Constitutional epimutation of the two major mismatch repair genes, MLH<\/jats:styled-content>1<\/jats:italic> and MSH<\/jats:styled-content>2<\/jats:italic>, has been identified as an alternative mechanism that predisposes to the development of Lynch syndrome. In the present work, we aimed to investigate the prevalence of MLH<\/jats:styled-content>1<\/jats:italic> constitutional methylation in colorectal cancer (CRC<\/jats:styled-content>) patients with abnormal expression of the MLH<\/jats:styled-content>1 protein in their tumors. In a series of 38 patients who met clinical criteria for Lynch syndrome genetic testing, with loss of MLH<\/jats:styled-content>1 expression in the tumor and with no germline mutations in the MLH<\/jats:styled-content>1<\/jats:italic> gene (35\/38) or with tumors presenting the BRAF<\/jats:styled-content><\/jats:italic> p.Val600Glu mutation (3\/38), we screened for constitutional methylation of the MLH<\/jats:styled-content>1<\/jats:italic> gene promoter using methylation\u2010specific multiplex ligation\u2010dependent probe amplification (MS<\/jats:styled-content>\u2010MLPA<\/jats:styled-content>) in various biological samples. We found four (4\/38; 10.5%) patients with constitutional methylation in the MLH<\/jats:styled-content>1<\/jats:italic> gene promoter. RNA<\/jats:styled-content> studies demonstrated decreased MLH<\/jats:styled-content>1<\/jats:italic> expression in the cases with constitutional methylation when compared with controls. We could infer the mosaic nature of MLH<\/jats:styled-content>1<\/jats:italic> constitutional hypermethylation in tissues originated from different embryonic germ layers, and in one family we could show that it occurred de novo. We conclude that constitutional MLH<\/jats:styled-content>1<\/jats:italic> methylation occurs in a significant proportion of patients who have loss of MLH<\/jats:styled-content>1 protein expression in their tumors and no MLH<\/jats:styled-content>1<\/jats:italic> pathogenic germline mutation. Furthermore, we provide evidence that MLH<\/jats:styled-content>1<\/jats:italic> constitutional hypermethylation is the molecular mechanism behind about 3% of Lynch syndrome families diagnosed in our institution, especially in patients with early onset or multiple primary tumors without significant family history.<\/jats:p>","DOI":"10.1002\/cam4.1285","type":"journal-article","created":{"date-parts":[[2018,1,17]],"date-time":"2018-01-17T06:46:10Z","timestamp":1516171570000},"page":"433-444","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Contribution of MLH<\/scp>1<\/i> constitutional methylation for Lynch syndrome diagnosis in patients with tumor MLH<\/scp>1 downregulation"],"prefix":"10.1002","volume":"7","author":[{"given":"Diana","family":"Pinto","sequence":"first","affiliation":[{"name":"Cancer Genetics Group IPO Porto Research Center (CI\u2010IPOP) Portuguese Oncology Institute of Porto (IPO Porto) Porto 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Portuguese Oncology Institute of Porto (IPO Porto) Porto Portugal"},{"name":"Department of Genetics Portuguese Oncology Institute of Porto (IPO Porto) Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Lopes","sequence":"additional","affiliation":[{"name":"Department of Pathology Portuguese Oncology Institute of Porto (IPO Porto) Porto Portugal"},{"name":"Cancer Biology and Epigenetics Group IPO Porto Research Center (CI\u2010IPOP) Portuguese Oncology Institute of Porto (IPO Porto) Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ragnhild","family":"Lothe","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Institute for Cancer Research Oslo University Hospital Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guro Elisabeth","family":"Lind","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Institute for Cancer Research Oslo 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