Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated "Big Bang" pathway to CRC in three of the four Lynch syndromes.
MLH1
MSH2
MSH6
PMS2
Adenoma
Colonoscopy
Colorectal
Lynch syndromes
MSI
Sojourn time
cancer
dMMR
Journal
Hereditary cancer in clinical practice
ISSN: 1731-2302
Titre abrégé: Hered Cancer Clin Pract
Pays: Poland
ID NLM: 101231179
Informations de publication
Date de publication:
13 May 2024
13 May 2024
Historique:
received:
08
04
2024
accepted:
04
05
2024
medline:
14
5
2024
pubmed:
14
5
2024
entrez:
13
5
2024
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
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.
Identifiants
pubmed: 38741120
doi: 10.1186/s13053-024-00279-3
pii: 10.1186/s13053-024-00279-3
doi:
Types de publication
Journal Article
Langues
eng
Pagination
6Subventions
Organisme : The Norwegian Cancer Society
ID : Contract 194751-2017
Organisme : The Norwegian Cancer Society
ID : Contract 194751-2017
Organisme : The Norwegian Cancer Society
ID : Contract 194751-2017
Organisme : Manchester National Institute for Health Research (NIHR) Biomedical Research Centre
ID : IS-BRC-1215-20007
Organisme : Manchester National Institute for Health Research (NIHR) Biomedical Research Centre
ID : IS-BRC-1215-20007
Informations de copyright
© 2024. The Author(s).
Références
Møller P, Seppälä TT, Ahadova A, et al. Dominantly inherited micro-satellite instable cancer - the four Lynch syndromes - an EHTG, PLSD position statement. Hered Cancer Clin Pract. 2023;21(1):19. https://doi.org/10.1186/s13053-023-00263-3 . PMID: 37821984; PMCID: PMC10568908. https://pubmed.ncbi.nlm.nih.gov/37821984/ .
doi: 10.1186/s13053-023-00263-3
pubmed: 37821984
pmcid: 10568908
https://www.omim.org/ Accessed April 2nd 2024.
Chan TA, Wang Z, Dang LH, Vogelstein B, Kinzler KW. Targeted inactivation of CTNNB1 reveals unexpected effects of beta-catenin mutation. Proc Natl Acad Sci U S A. 2002;99(12):8265–70. https://doi.org/10.1073/pnas.082240999 . PMID: 12060769; PMCID: PMC123056. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC123056/ .
doi: 10.1073/pnas.082240999
pubmed: 12060769
pmcid: 123056
Segditsas S, Tomlinson I. Colorectal cancer and genetic alterations in the wnt pathway. Oncogene. 2006;25:7531–7. https://doi.org/10.1038/sj.onc.1210059 .
doi: 10.1038/sj.onc.1210059
pubmed: 17143297
Jass JR, Stewart SM. Evolution of hereditary non-polyposis colorectal cancer. Gut. 1992;33(6):783–6. https://doi.org/10.1136/gut.33.6.783 . PMID: 1624160; PMCID: PMC1379336. https://pubmed.ncbi.nlm.nih.gov/1624160/ .
doi: 10.1136/gut.33.6.783
pubmed: 1624160
pmcid: 1379336
Ahadova A, Gallon R, Gebert J, et al. Three molecular pathways model colorectal carcinogenesis in Lynch syndrome. Int J Cancer. 2018;143(1):139–50. https://doi.org/10.1002/ijc.31300 . Epub 2018 Feb 23. PMID:. https://pubmed.ncbi.nlm.nih.gov/29424427/ .
doi: 10.1002/ijc.31300
pubmed: 29424427
Hans FA, Vasen I, Blanco K, Aktan-Collan, et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut. 2013;62:812–23. https://doi.org/10.1136/gutjnl-2012-304356 . https://gut.bmj.com/content/gutjnl/62/6/812.full.pdf .
doi: 10.1136/gutjnl-2012-304356
Engel C, Vasen HF, Seppälä T et al. No Difference in Colorectal Cancer Incidence or Stage at Detection by Colonoscopy Among 3 Countries With Different Lynch Syndrome Surveillance Policies. Gastroenterology. 2018;155(5):1400–1409.e2. https://doi.org/10.1053/j.gastro.2018.07.030 . Epub 2018 Jul 29. PMID: 30063918. https://pubmed.ncbi.nlm.nih.gov/30063918/ .
Seppälä TT, Ahadova A, Dominguez-Valentin M, et al. Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report. Hered Cancer Clin Pract. 2019;17:8. https://doi.org/10.1186/s13053-019-0106-8 . PMID: 30858900; PMCID: PMC6394091. https://pubmed.ncbi.nlm.nih.gov/30858900/ .
doi: 10.1186/s13053-019-0106-8
pubmed: 30858900
pmcid: 6394091
Møller P, Seppälä T, Dowty JG, et al. Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium. Hered Cancer Clin Pract. 2022;20(1):36. https://doi.org/10.1186/s13053-022-00241-1 . PMID: 36182917; PMCID: PMC9526951. https://pubmed.ncbi.nlm.nih.gov/36182917/ .
doi: 10.1186/s13053-022-00241-1
pubmed: 36182917
pmcid: 9526951
Bonadona V, Bonaïti B, Olschwang S et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305(22):2304-10. https://doi.org/10.1001/jama.2011.743 . PMID: 21642682. https://pubmed.ncbi.nlm.nih.gov/21642682/ .
Hampel H, Stephens JA, Pukkala E, Sankila R, Aaltonen LA, Mecklin JP, de la Chapelle A. Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology. 2005;129(2):415 – 21. https://doi.org/10.1016/j.gastro.2005.05.011 . PMID: 16083698. https://pubmed.ncbi.nlm.nih.gov/16083698/ .
Baglietto L, Lindor NM, Dowty JG, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010;102(3):193–201. https://doi.org/10.1093/jnci/djp473 . Epub 2009 Dec 22. PMID: 20028993; PMCID: PMC2815724. https://pubmed.ncbi.nlm.nih.gov/20028993/ .
doi: 10.1093/jnci/djp473
pubmed: 20028993
pmcid: 2815724
Ten Broeke SW, van der Klift HM, Tops CMJ et al. Cancer Risks for PMS2-Associated Lynch Syndrome. J Clin Oncol. 2018;36(29):2961–2968. doi: 10.1200/JCO.2018.78.4777. Epub 2018 Aug 30. Erratum in: J Clin Oncol. 2019;37(9):761. PMID: 30161022; PMCID: PMC6349460. https://pubmed.ncbi.nlm.nih.gov/30161022/ .
Kloor M, Huth C, Voigt AY, Benner A, Schirmacher P, von Knebel Doeberitz M, Bläker H. Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study. Lancet Oncol. 2012;13(6):598–606. doi: 10.1016/S1470-2045(12)70109-2. Epub 2012 May 1. PMID: 22552011. https://pubmed.ncbi.nlm.nih.gov/22552011/ .
Pai RK, Dudley B, Karloski E, et al. DNA mismatch repair protein deficient non-neoplastic colonic crypts: a novel indicator of Lynch syndrome. Mod Pathol. 2018;31(10):1608–18. https://doi.org/10.1038/s41379-018-0079-6 . Epub 2018 Jun 8. PMID: 29884888; PMCID: PMC6396289. https://pubmed.ncbi.nlm.nih.gov/29884888/ .
doi: 10.1038/s41379-018-0079-6
pubmed: 29884888
pmcid: 6396289
Brand RE, Dudley B, Karloski E, Das R, Fuhrer K, Pai RK, Pai RK. Detection of DNA mismatch repair deficient crypts in random colonoscopic biopsies identifies Lynch syndrome patients. Fam Cancer. 2020;19(2):169–175. https://doi.org/10.1007/s10689-020-00161-w . PMID: 31997046. https://pubmed.ncbi.nlm.nih.gov/31997046/ .
Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in Mismatch Repair-Deficient, locally advanced rectal Cancer. N Engl J Med. 2022;386(25):2363–76. https://doi.org/10.1056/NEJMoa2201445 . Epub 2022 Jun 5. PMID: 35660797; PMCID: PMC9492301. https://pubmed.ncbi.nlm.nih.gov/35660797/ .
doi: 10.1056/NEJMoa2201445
pubmed: 35660797
pmcid: 9492301
Ahadova A, Seppälä TT, Engel C et al. The unnatural history of colorectal cancer in Lynch syndrome: Lessons from colonoscopy surveillance. Int J Cancer. 2021;148(4):800–811. doi: 10.1002/ijc.33224. Epub 2020 Aug 3. PMID: 32683684. https://pubmed.ncbi.nlm.nih.gov/32683684/ .
Haupt S, Zeilmann A, Ahadova A, Bläker H, von Knebel Doeberitz M, Kloor M, Heuveline V. Mathematical modeling of multiple pathways in colorectal carcinogenesis using dynamical systems with Kronecker structure. PLoS Comput Biol. 2021;17(5):e1008970. https://doi.org/10.1371/journal.pcbi.1008970 . PMID: 34003820; PMCID: PMC8162698. https://pubmed.ncbi.nlm.nih.gov/34003820/ .
Møller P, Seppälä T, Bernstein I, et al. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut. 2017;66(3):464–72. Epub 2015 Dec 9. PMID: 26657901; PMCID: PMC5534760. https://pubmed.ncbi.nlm.nih.gov/26657901/ . doi: 10.1136/gutjnl-2015-309675.
doi: 10.1136/gutjnl-2015-309675
pubmed: 26657901
Møller P. The prospective Lynch Syndrome Database: background, design, main results and complete MySQL code. Hered Cancer Clin Pract. 2022;20(1):37. https://doi.org/10.1186/s13053-022-00243-z . PMID: 36411472; PMCID: PMC9677689. https://pubmed.ncbi.nlm.nih.gov/36411472/ .
doi: 10.1186/s13053-022-00243-z
pubmed: 36411472
pmcid: 9677689
Møller P. The prospective Lynch Syndrome database reports enable evidence-based personal precision health care. Hered Cancer Clin Pract. 2020;18:6. https://doi.org/10.1186/s13053-020-0138-0 . PMID: 32190163; PMCID: PMC7073013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073013/ .
doi: 10.1186/s13053-020-0138-0
pubmed: 32190163
pmcid: 7073013
Dominguez-Valentin M, Haupt S, Seppälä TT et al. Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database. EClinicalMedicine. 2023;58:101909. https://doi.org/10.1016/j.eclinm.2023.101909 . PMID: 37181409; PMCID: PMC10166779. https://pubmed.ncbi.nlm.nih.gov/37181409/ .
https:// en.wikipedia.org/wiki/Mean_sojourn_time Accessed April 2nd 2024.
Prevost TC, Launoy G, Duffy SW, Chen HH. Estimating sensitivity and sojourn time in screening for colorectal cancer: a comparison of statistical approaches. Am J Epidemiol. 1998;148(6):609 – 19. https://doi.org/10.1093/oxfordjournals.aje.a009687 . PMID: 9753016. https://pubmed.ncbi.nlm.nih.gov/9753016/ .
https:// en.wikipedia.org/wiki/Poisson_distribution Accessed April 2nd 2024.
https:// www.britannica.com/science/stochastic-process Accessed April 2nd 2024.
https:// en.wikipedia.org/wiki/Introduction_to_quantum_mechanics Accessed April 2nd 2024.
Annelie Liljegren G, Barker F, Elliott et al. Polyps in Mismatch Repair Mutation Carriers Among CAPP2 Participants: Report by the Colorectal Adenoma/Carcinoma Prevention Programme 2. JCO. 2008; 26; 20; 3434-9 https://doi.org/10.1200/JCO.2007.13.2795 .
Ahadova A, von Knebel Doeberitz M, Bläker H et al. CTNNB1-mutant colorectal carcinomas with immediate invasive growth: a model of interval cancers in Lynch syndrome. Familial Cancer 15, 579–586 (2016). https://doi.org/10.1007/s10689 -016-9899-z https://link.springer.com/article/10.1007/s10689-016-9899-z.
Ahadova A, Stenzinger A, Seppälä T, Hüneburg R, Kloor M, Bläker H. Lynpath Investigators. A Two-in-One Hit Model of Shortcut Carcinogenesis in MLH1 Lynch Syndrome Carriers. Gastroenterology. 2023;165(1):267–270.e4. https://doi.org/10.1053/j.gastro.2023.03.007 . Epub 2023 Mar 11. PMID: 36907525. https://pubmed.ncbi.nlm.nih.gov/36907525/ .
Helderman NC, Van Der Werf-‘t Lam AS, MSH6 TUMOR GROUP, Morreau H, Boot A, Van Wezel T, Nielsen M. Gastroenterology. 2023;165(1):271–e2742. https://doi.org/10.1053/j.gastro.2023.03.198 . Epub 2023 Mar 15. PMID: 36931573. https://pubmed.ncbi.nlm.nih.gov/36931573/ . Molecular Profile of MSH6-Associated Colorectal Carcinomas Shows Distinct Features From Other Lynch Syndrome-Associated Colorectal Carcinomas.
Ten Broeke SW, van Bavel TC, Jansen AML et al. Molecular Background of Colorectal Tumors From Patients With Lynch Syndrome Associated With Germline Variants in PMS2. Gastroenterology. 2018;155(3):844–851. https://doi.org/10.1053/j.gastro.2018.05.020 . Epub 2018 Jul 29. PMID: 29758216. https://pubmed.ncbi.nlm.nih.gov/29758216/ .
https:// www.google.com/search?client=firefox-b-d&q=heisenberg+uncertainty+principle Accessed April 2nd 2024.
Staffa L, Echterdiek F, Nelius N, et al. Mismatch repair-deficient crypt foci in Lynch syndrome–molecular alterations and association with clinical parameters. PLoS ONE. 2015;10(3):e0121980. https://doi.org/10.1371/journal.pone.0121980 . PMID: 25816162; PMCID: PMC4376900. https://pubmed.ncbi.nlm.nih.gov/25816162/ .
doi: 10.1371/journal.pone.0121980
pubmed: 25816162
pmcid: 4376900
Sottoriva A, Kang H, Ma Z, et al. A Big Bang model of human colorectal tumor growth. Nat Genet. 2015;47:209–16. https://doi.org/10.1038/ng.3214 . https://www.nature.com/articles/ng.3214 .
doi: 10.1038/ng.3214
pubmed: 25665006
pmcid: 4575589
Chien J, Neums L, Powell AFLA, Torres M, Kalli KR, Multinu F, Shridhar V, Mariani A. Genetic Evidence for Early Peritoneal Spreading in Pelvic High-Grade Serous Cancer. Front Oncol. 2018;8:58. https://doi.org/10.3389/fonc.2018.00058 . PMID: 29594039; PMCID: PMC5858520. https://pubmed.ncbi.nlm.nih.gov/29594039/ .
Dominguez-Valentin M, Seppälä TT, Sampson JR, et al. Survival by colon cancer stage and screening interval in Lynch syndrome: a prospective Lynch syndrome database report. Hered Cancer Clin Pract. 2019;17:28. https://doi.org/10.1186/s13053-019-0127-3 . PMID: 31636762; PMCID: PMC6792227. https://pubmed.ncbi.nlm.nih.gov/31636762/ .
doi: 10.1186/s13053-019-0127-3
pubmed: 31636762
pmcid: 6792227
Mangas-Sanjuan C, de-Castro L, Cubiella J et al. Role of Artificial Intelligence in Colonoscopy Detection of Advanced Neoplasias: A Randomized Trial. Ann Intern Med. 2023;176(9):1145–1152. doi: 10.7326/M22-2619. Epub 2023 Aug 29. PMID: 37639723. https://pubmed.ncbi.nlm.nih.gov/37639723/ .
Hüneburg R, Bucksch K, Schmeißer F, et al. Real-time use of artificial intelligence (CADEYE) in colorectal cancer surveillance of patients with Lynch syndrome-A randomized controlled pilot trial (CADLY). United Eur Gastroenterol J. 2023;11(1):60–8. https://doi.org/10.1002/ueg2.12354 . Epub 2022 Dec 26. PMID: 36571259; PMCID: PMC9892476. https://pubmed.ncbi.nlm.nih.gov/36571259/ .
doi: 10.1002/ueg2.12354
Sánchez A, Roos VH, Navarro M et al. Quality of Colonoscopy Is Associated With Adenoma Detection and Postcolonoscopy Colorectal Cancer Prevention in Lynch Syndrome. Clin Gastroenterol Hepatol. 2022;20(3):611–621.e9. https://doi.org/10.1016/j.cgh.2020.11.002 . Epub 2020 Nov 3. PMID: 33157315. https://pubmed.ncbi.nlm.nih.gov/33157315/ .
Sleiman J, Farha N, Beard J et al. Incidence and prevalence of advanced colorectal neoplasia in Lynch syndrome. Gastrointest Endosc. 2023;98(3):412–419.e8. https://doi.org/10.1016/j.gie.2023.04.001 . Epub 2023 Apr 7. PMID: 37031913. https://pubmed.ncbi.nlm.nih.gov/37031913/ .
Aronson M, Gryfe R, Choi YH, et al. Evaluating colonoscopy screening intervals in patients with Lynch syndrome from a large Canadian registry. J Natl Cancer Inst. 2023;115(7):778–87. https://doi.org/10.1093/jnci/djad058 . PMID: 36964717; PMCID: PMC10323893. https://pubmed.ncbi.nlm.nih.gov/36964717/ .
doi: 10.1093/jnci/djad058
pubmed: 36964717
pmcid: 10323893
Del Carmen G, Reyes-Uribe L, Goyco D, et al. Colorectal surveillance outcomes from an institutional longitudinal cohort of lynch syndrome carriers. Front Oncol. 2023;13:1146825. https://doi.org/10.3389/fonc.2023.1146825 . PMID: 37168379; PMCID: PMC10164917. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10164917/ .
doi: 10.3389/fonc.2023.1146825
pubmed: 37168379
pmcid: 10164917
Henry T, Lync JF, Lynch R, Fitzgibbons. Jr. Role of prophylactic colectomy in Lynch Syndrome. Clin Colorectal Cancer. 2003,3;2; 99-101August 2003; 99 https://www.sciencedirect.com/science/article/pii/S1533002811700743?via%3Dihub .
Cavestro GM, Mannucci A, Balaguer F, et al. Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management guidelines. Clin Gastroenterol Hepatol. 2023;21(3):581–e60333. https://doi.org/10.1016/j.cgh.2022.12.006 . Epub 2022 Dec 20. PMID:. https://pubmed.ncbi.nlm.nih.gov/36549470/ .
doi: 10.1016/j.cgh.2022.12.006
pubmed: 36549470
Seppälä TT, Latchford A, Negoi I et al. European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender. Br J Surg. 2021;108(5):484–498. https://doi.org/10.1002/bjs.11902 . PMID: 34043773; PMCID: PMC10364896. https://pubmed.ncbi.nlm.nih.gov/34043773/ .