Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Carnevali, Ileana Wanda, Cini, Giulia, Libera, Laura, Sahnane, Nora, Facchi, Sofia, Viel, Alessandra, Sessa, Fausto, Tibiletti, Maria Grazia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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
_version_ 1785140038019842048
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
work_keys_str_mv AT carnevaliileanawanda mlh1promotermethylationcouldbethesecondhitinlynchsyndromecarcinogenesis
AT cinigiulia mlh1promotermethylationcouldbethesecondhitinlynchsyndromecarcinogenesis
AT liberalaura mlh1promotermethylationcouldbethesecondhitinlynchsyndromecarcinogenesis
AT sahnanenora mlh1promotermethylationcouldbethesecondhitinlynchsyndromecarcinogenesis
AT facchisofia mlh1promotermethylationcouldbethesecondhitinlynchsyndromecarcinogenesis
AT vielalessandra mlh1promotermethylationcouldbethesecondhitinlynchsyndromecarcinogenesis
AT sessafausto mlh1promotermethylationcouldbethesecondhitinlynchsyndromecarcinogenesis
AT tibilettimariagrazia mlh1promotermethylationcouldbethesecondhitinlynchsyndromecarcinogenesis