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Volume 14
Issue 11
10.3390/genes14112060
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Article

MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis

by
Ileana Wanda Carnevali
1,2,*,
Giulia Cini
3,
Laura Libera
2,4,
Nora Sahnane
1,2,
Sofia Facchi
2,4,
Alessandra Viel
3,
Fausto Sessa
1,2,4 and
Maria Grazia Tibiletti
2
1
UO Anatomia Patologica Ospedale di Circolo ASST-Settelaghi, 21100 Varese, Italy
2
Centro di Ricerca per lo Studio dei Tumori Eredo-Famigliari, Università dell’Insubria, 21100 Varese, Italy
3
Unit of Functional Oncogenomics and Genetics, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
4
Department of Medicine and Thecnological Innovation, Università dell’Insubria, 21100 Varese, Italy
*
Author to whom correspondence should be addressed.
Genes 2023, 14(11), 2060; https://doi.org/10.3390/genes14112060
Submission received: 26 September 2023 / Revised: 3 November 2023 / Accepted: 7 November 2023 / Published: 9 November 2023
(This article belongs to the Special Issue Genetics and Genomics of Gastrointestinal Cancers: From Prevention to Treatment)
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Abstract

(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.
Keywords: Lynch syndrome; MLH1 methylation; constitutional epimutation; LS universal screening Lynch syndrome; MLH1 methylation; constitutional epimutation; LS universal screening

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MDPI and ACS Style

Carnevali, I.W.; Cini, G.; Libera, L.; Sahnane, N.; Facchi, S.; Viel, A.; Sessa, F.; Tibiletti, M.G. MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis. Genes 2023, 14, 2060. https://doi.org/10.3390/genes14112060

AMA Style

Carnevali IW, Cini G, Libera L, Sahnane N, Facchi S, Viel A, Sessa F, Tibiletti MG. MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis. Genes. 2023; 14(11):2060. https://doi.org/10.3390/genes14112060

Chicago/Turabian Style

Carnevali, Ileana Wanda, Giulia Cini, Laura Libera, Nora Sahnane, Sofia Facchi, Alessandra Viel, Fausto Sessa, and Maria Grazia Tibiletti. 2023. "MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis" Genes 14, no. 11: 2060. https://doi.org/10.3390/genes14112060

APA Style

Carnevali, I. W., Cini, G., Libera, L., Sahnane, N., Facchi, S., Viel, A., Sessa, F., & Tibiletti, M. G. (2023). MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis. Genes, 14(11), 2060. https://doi.org/10.3390/genes14112060

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