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Lookup NU author(s): Professor Sir John BurnORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024.Background: Colorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate, the success of colonoscopy in preventing CRC would be a function of the intervals between colonoscopies and mean sojourn time of detectable adenomas. Contrary to expectations, colonoscopy did not decrease incidence of CRC in the Lynch syndromes and shorter colonoscopy intervals have not been effective in reducing CRC incidence. The prospective Lynch Syndrome Database (PLSD) was designed to examine these issues in carriers of pathogenic variants of the mis-match repair (path_MMR) genes. Materials and methods: We examined the CRC and colorectal adenoma incidences in 3,574 path_MLH1, path_MSH2, path_MSH6 and path_PMS2 carriers subjected to regular colonoscopy with polypectomy, and considered the results based on sojourn times and stochastic probability paradigms. Results: Most of the path_MMR carriers in each genetic group had no adenomas. There was no association between incidences of CRC and the presence of adenomas. There was no CRC observed in path_PMS2 carriers. Conclusions: Colonoscopy prevented CRC in path_PMS2 carriers but not in the others. Our findings are consistent with colonoscopy surveillance blocking the adenoma-carcinoma pathway by removing identified adenomas which might otherwise become CRCs. However, in the other carriers most CRCs likely arised from dMMR cells in the crypts that have an increased mutation rate with increased stochastic chaotic probabilities for mutations. Therefore, this mechanism, that may be associated with no or only a short sojourn time of MSI tumours as adenomas, could explain the findings in our previous and current reports.
Author(s): Moller P, Haupt S, Ahadova A, Kloor M, Sampson JR, Sunde L, Seppala T, Burn J, Bernstein I, Capella G, Evans DG, Lindblom A, Winship I, Macrae F, Katz L, Laish I, Vainer E, Monahan K, Half E, Horisberger K, da Silva LA, Heuveline V, Therkildsen C, Lautrup C, Klarskov LL, Cavestro GM, Moslein G, Hovig E, Dominguez-Valentin M
Publication type: Article
Publication status: Published
Journal: Hereditary Cancer in Clinical Practice
Year: 2024
Volume: 22
Issue: 1
Online publication date: 13/05/2024
Acceptance date: 04/05/2024
Date deposited: 30/05/2024
ISSN (print): 1731-2302
ISSN (electronic): 1897-4287
Publisher: BioMed Central Ltd
URL: https://doi.org/10.1186/s13053-024-00279-3
DOI: 10.1186/s13053-024-00279-3
Data Access Statement: The tables are the raw data grouped as indicated. Figure 1 is based on Table 2. The complete SQL code for how the grouped data underlying Fig. 3 was extracted from the MySQL database is published in reference #22. Anonymized data underlying Fig. 2, the annual incidences by age group underlying Fig. 3 are available upon request, both pending written agreement that none of these will be used for any other purpose than confirming the figures to be correct.
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