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Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement

Møller, Pal, Seppälä, Toni T., Ahadova, Aysel, Crosbie, Emma J., Holinski-Feder, Elke, Scott, Rodney, Haupt, Saskia, Möslein, Gabriela, Winship, Ingrid, Broeke, Sanne W. Bajwa-ten, Kohut, Kelly E., Ryan, Neil, Bauerfeind, Peter, Thomas, Laura E., Evans, D. Gareth, Aretz, Stefan, Sijmons, Rolf H., Half, Elizabeth, Heinimann, Karl, Horisberger, Karoline, Monahan, Kevin, Engel, Christoph, Cavestro, Giulia Martina, Fruscio, Robert, Abu-Freha, Naim, Zohar, Levi, Laghi, Luigi, Bertario, Lucio, Bonanni, Bernardo, Tibiletti, Maria Grazia, Lino-Silva, Leonardo S., Vaccaro, Carlos, Valle, Adriana Della, Rossi, Benedito Mauro, da Silva, Leandro Apolinário, de Oliveira Nascimento, Ivana Lucia, Rossi, Norma Teresa, Dębniak, Tadeusz, Mecklin, Jukka-Pekka, Bernstein, Inge, Lindblom, Annika, Sunde, Lone, Nakken, Sigve, Heuveline, Vincent, Burn, John, Hovig, Eivind, Kloor, Matthias, Sampson, Julian R. ORCID: and Dominguez-Valentin, Mev 2023. Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement. Hereditary Cancer in Clinical Practice 21 (1) , 19. 10.1186/s13053-023-00263-3

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The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an “average sex “or a pathogenic variant in an “average Lynch syndrome gene” and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host’s adaptive immune system’s ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system’s capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Additional Information: License information from Publisher: LICENSE 1: URL:, Type: open-access
Publisher: BioMed Central
Date of First Compliant Deposit: 13 October 2023
Date of Acceptance: 29 September 2023
Last Modified: 13 Oct 2023 08:15

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