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Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement
,
D. Gareth Evans,
Stefan Aretz,
Rolf H. Sijmons,
Elizabeth Half,
Karl Heinimann,
Karoline Horisberger,
Kevin Monahan,
Christoph Engel,
Giulia Martina Cavestro,
Robert Fruscio,
Naim Abu-Freha,
Levi Zohar,
Luigi Laghi,
Lucio Bertario,
Bernardo Bonanni,
Maria Grazia Tibiletti,
Leonardo S. Lino-Silva,
Carlos Vaccaro,
Adriana Della Valle,
Benedito Mauro Rossi,
Leandro Apolinário da Silva,
Ivana Lucia de Oliveira Nascimento,
Norma Teresa Rossi,
Tadeusz Dębniak,
Jukka-Pekka Mecklin,
Inge Bernstein,
Annika Lindblom,
Lone Sunde,
Sigve Nakken,
Vincent Heuveline,
John Burn,
Eivind Hovig,
Matthias Kloor,
Julian R. Sampson,
Mev Dominguez-Valentin,
(On behalf of the Prospective Lynch Syndrome Database (www.plsd.eu) and The European Hereditary Tumour Group (www.ehtg.org))
Hereditary Cancer in Clinical Practice, Volume: 21, Issue: 1
Swansea University Author:
Laura Thomas
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DOI (Published version): 10.1186/s13053-023-00263-3
Abstract
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...
| Published in: | Hereditary Cancer in Clinical Practice |
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| ISSN: | 1897-4287 |
| Published: |
Springer Science and Business Media LLC
2023
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa64733 |
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| Abstract: |
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. |
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| Keywords: |
Dominantly inherited micro-satellite instable cancers, MSI cancers, mismatch repair genes, Lynch syndromes |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Issue: |
1 |