{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T18:21:57Z","timestamp":1792693317815,"version":"4.5.0"},"reference-count":27,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T00:00:00Z","timestamp":1699488000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>(1) Background: MLH1 hypermethylation is an epigenetic alteration in the tumorigenesis of colorectal cancer (CRC) and endometrial cancer (EC), causing gene silencing, and, as a consequence, microsatellite instability. Commonly, MLH1 hypermethylation is considered a somatic and sporadic event in cancer, and its detection is recognized as a useful tool to distinguish sporadic from inherited conditions (such as, Lynch syndrome (LS)). However, MLH1 hypermethylation has been described in rare cases of CRC and EC in LS patients. (2) Methods: A total of 61 cancers (31 CRCs, 27 ECs, 2 ovarian cancers, and 1 stomach cancer) from 56 patients referred to cancer genetic counselling were selected for loss of MLH1 protein expression and microsatellite instability. All cases were investigated for MLH1 promoter methylation and MLH1\/PMS2 germline variants. (3) Results: Somatic MLH1 promoter hypermethylation was identified in 16.7% of CRC and in 40% of EC carriers of MLH1 germline pathogenic variants. In two families, primary and secondary MLH1 epimutations were demonstrated. (4) Conclusions: MLH1 hypermethylation should not be exclusively considered as a sporadic cancer mechanism, as a non-negligible number of LS-related cancers are MLH1 hypermethylated. Current flow charts for universal LS screening, which include MLH1 methylation, should be applied, paying attention to a patient\u2019s family and personal history.<\/jats:p>","DOI":"10.3390\/genes14112060","type":"journal-article","created":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T10:19:27Z","timestamp":1699525167000},"page":"2060","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0511-5427","authenticated-orcid":false,"given":"Ileana Wanda","family":"Carnevali","sequence":"first","affiliation":[{"name":"UO Anatomia Patologica Ospedale di Circolo ASST-Settelaghi, 21100 Varese, Italy"},{"name":"Centro di Ricerca per lo Studio dei Tumori Eredo-Famigliari, Universit\u00e0 dell\u2019Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Cini","sequence":"additional","affiliation":[{"name":"Unit of Functional Oncogenomics and Genetics, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2130-6669","authenticated-orcid":false,"given":"Laura","family":"Libera","sequence":"additional","affiliation":[{"name":"Centro di Ricerca per lo Studio dei Tumori Eredo-Famigliari, Universit\u00e0 dell\u2019Insubria, 21100 Varese, Italy"},{"name":"Department of Medicine and Thecnological Innovation, Universit\u00e0 dell\u2019Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora","family":"Sahnane","sequence":"additional","affiliation":[{"name":"UO Anatomia Patologica Ospedale di Circolo ASST-Settelaghi, 21100 Varese, Italy"},{"name":"Centro di Ricerca per lo Studio dei Tumori Eredo-Famigliari, Universit\u00e0 dell\u2019Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Facchi","sequence":"additional","affiliation":[{"name":"Centro di Ricerca per lo Studio dei Tumori Eredo-Famigliari, Universit\u00e0 dell\u2019Insubria, 21100 Varese, Italy"},{"name":"Department of Medicine and Thecnological Innovation, Universit\u00e0 dell\u2019Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2804-0840","authenticated-orcid":false,"given":"Alessandra","family":"Viel","sequence":"additional","affiliation":[{"name":"Unit of Functional Oncogenomics and Genetics, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fausto","family":"Sessa","sequence":"additional","affiliation":[{"name":"UO Anatomia Patologica Ospedale di Circolo ASST-Settelaghi, 21100 Varese, Italy"},{"name":"Centro di Ricerca per lo Studio dei Tumori Eredo-Famigliari, Universit\u00e0 dell\u2019Insubria, 21100 Varese, Italy"},{"name":"Department of Medicine and Thecnological Innovation, Universit\u00e0 dell\u2019Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Grazia","family":"Tibiletti","sequence":"additional","affiliation":[{"name":"Centro di Ricerca per lo Studio dei Tumori Eredo-Famigliari, Universit\u00e0 dell\u2019Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"American College of Obstetricians and Gynecologists (ACOG) Committee (2019). 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