<i>MLH1</i> Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis
(1) Background: <i>MLH1</i> 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, <i>MLH1</i> hypermethylation is considere...
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MDPI AG
2023-11-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/14/11/2060 |
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| author | Ileana Wanda Carnevali Giulia Cini Laura Libera Nora Sahnane Sofia Facchi Alessandra Viel Fausto Sessa Maria Grazia Tibiletti |
| author_facet | Ileana Wanda Carnevali Giulia Cini Laura Libera Nora Sahnane Sofia Facchi Alessandra Viel Fausto Sessa Maria Grazia Tibiletti |
| author_sort | Ileana Wanda Carnevali |
| collection | DOAJ |
| description | (1) Background: <i>MLH1</i> 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, <i>MLH1</i> 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, <i>MLH1</i> 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 <i>MLH1</i> protein expression and microsatellite instability. All cases were investigated for <i>MLH1</i> promoter methylation and <i>MLH1/PMS2</i> germline variants. (3) Results: Somatic <i>MLH1</i> promoter hypermethylation was identified in 16.7% of CRC and in 40% of EC carriers of <i>MLH1</i> germline pathogenic variants. In two families, primary and secondary <i>MLH1</i> epimutations were demonstrated. (4) Conclusions: <i>MLH1</i> hypermethylation should not be exclusively considered as a sporadic cancer mechanism, as a non-negligible number of LS-related cancers are <i>MLH1</i> hypermethylated. Current flow charts for universal LS screening, which include <i>MLH1</i> methylation, should be applied, paying attention to a patient’s family and personal history. |
| first_indexed | 2024-03-09T16:48:24Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-09T16:48:24Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-eff9ea9bb63d41269124e502148c00822023-11-24T14:44:01ZengMDPI AGGenes2073-44252023-11-011411206010.3390/genes14112060<i>MLH1</i> Promoter Methylation Could Be the Second Hit in Lynch Syndrome CarcinogenesisIleana Wanda Carnevali0Giulia Cini1Laura Libera2Nora Sahnane3Sofia Facchi4Alessandra Viel5Fausto Sessa6Maria Grazia Tibiletti7UO Anatomia Patologica Ospedale di Circolo ASST-Settelaghi, 21100 Varese, ItalyUnit of Functional Oncogenomics and Genetics, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, ItalyCentro di Ricerca per lo Studio dei Tumori Eredo-Famigliari, Università dell’Insubria, 21100 Varese, ItalyUO Anatomia Patologica Ospedale di Circolo ASST-Settelaghi, 21100 Varese, ItalyCentro di Ricerca per lo Studio dei Tumori Eredo-Famigliari, Università dell’Insubria, 21100 Varese, ItalyUnit of Functional Oncogenomics and Genetics, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, ItalyUO Anatomia Patologica Ospedale di Circolo ASST-Settelaghi, 21100 Varese, ItalyCentro di Ricerca per lo Studio dei Tumori Eredo-Famigliari, Università dell’Insubria, 21100 Varese, Italy(1) Background: <i>MLH1</i> 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, <i>MLH1</i> 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, <i>MLH1</i> 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 <i>MLH1</i> protein expression and microsatellite instability. All cases were investigated for <i>MLH1</i> promoter methylation and <i>MLH1/PMS2</i> germline variants. (3) Results: Somatic <i>MLH1</i> promoter hypermethylation was identified in 16.7% of CRC and in 40% of EC carriers of <i>MLH1</i> germline pathogenic variants. In two families, primary and secondary <i>MLH1</i> epimutations were demonstrated. (4) Conclusions: <i>MLH1</i> hypermethylation should not be exclusively considered as a sporadic cancer mechanism, as a non-negligible number of LS-related cancers are <i>MLH1</i> hypermethylated. Current flow charts for universal LS screening, which include <i>MLH1</i> methylation, should be applied, paying attention to a patient’s family and personal history.https://www.mdpi.com/2073-4425/14/11/2060Lynch syndrome<i>MLH1</i> methylationconstitutional epimutationLS universal screening |
| spellingShingle | Ileana Wanda Carnevali Giulia Cini Laura Libera Nora Sahnane Sofia Facchi Alessandra Viel Fausto Sessa Maria Grazia Tibiletti <i>MLH1</i> Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis Genes Lynch syndrome <i>MLH1</i> methylation constitutional epimutation LS universal screening |
| title | <i>MLH1</i> Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis |
| title_full | <i>MLH1</i> Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis |
| title_fullStr | <i>MLH1</i> Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis |
| title_full_unstemmed | <i>MLH1</i> Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis |
| title_short | <i>MLH1</i> Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis |
| title_sort | i mlh1 i promoter methylation could be the second hit in lynch syndrome carcinogenesis |
| topic | Lynch syndrome <i>MLH1</i> methylation constitutional epimutation LS universal screening |
| url | https://www.mdpi.com/2073-4425/14/11/2060 |
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