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MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis
(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 canc...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10670941/ https://www.ncbi.nlm.nih.gov/pubmed/38003003 http://dx.doi.org/10.3390/genes14112060 |
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author | Carnevali, Ileana Wanda Cini, Giulia Libera, Laura Sahnane, Nora Facchi, Sofia Viel, Alessandra Sessa, Fausto Tibiletti, Maria Grazia |
author_facet | Carnevali, Ileana Wanda Cini, Giulia Libera, Laura Sahnane, Nora Facchi, Sofia Viel, Alessandra Sessa, Fausto Tibiletti, Maria Grazia |
author_sort | Carnevali, Ileana Wanda |
collection | PubMed |
description | (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’s family and personal history. |
format | Online Article Text |
id | pubmed-10670941 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-106709412023-11-09 MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis Carnevali, Ileana Wanda Cini, Giulia Libera, Laura Sahnane, Nora Facchi, Sofia Viel, Alessandra Sessa, Fausto Tibiletti, Maria Grazia Genes (Basel) Article (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’s family and personal history. MDPI 2023-11-09 /pmc/articles/PMC10670941/ /pubmed/38003003 http://dx.doi.org/10.3390/genes14112060 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Carnevali, Ileana Wanda Cini, Giulia Libera, Laura Sahnane, Nora Facchi, Sofia Viel, Alessandra Sessa, Fausto Tibiletti, Maria Grazia MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis |
title | MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis |
title_full | MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis |
title_fullStr | MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis |
title_full_unstemmed | MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis |
title_short | MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis |
title_sort | mlh1 promoter methylation could be the second hit in lynch syndrome carcinogenesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10670941/ https://www.ncbi.nlm.nih.gov/pubmed/38003003 http://dx.doi.org/10.3390/genes14112060 |
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