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Original article

Vol. 155 No. 7 (2025)

From gaps to compliance: a 12-year retrospective cohort study of trends in mismatch repair protein testing and Lynch syndrome identification in colorectal cancer in Central Switzerland

Cite this as:
Swiss Med Wkly. 2025;155:4345
Published
14.07.2025

Summary

STUDY AIM: Alongside an analysis of incidence trends in colorectal cancer and Lynch syndrome over time, the study sought to evaluate the implementation and trends of reflex testing for mismatch repair proteins and key mutations in relevant genes (BRAF, KRAS, NRAS) in colorectal cancer in Central Switzerland from 2011 to 2022, specifically assessing adherence to the Swiss Academy for Quality in Medicine (SAQM) guidelines, in order to identify any gaps or inconsistencies in testing practices that may hinder the diagnosis of Lynch syndrome or microsatellite instability, highlighting areas requiring improvements for optimal patient care.

METHODS: This retrospective study enrolled 2602 patients with 2673 histologically confirmed colorectal cancers. Data collection from the Central Switzerland Cancer Registry included demographic, molecular and immunohistochemical profiles of all histologically confirmed colorectal cancers over the analysed 12-year period. Statistical analyses were performed using R (v4.3.1) with the tidyverse package. Normality was assessed with the Shapiro-Wilk test and non-parametric comparisons were made using the Wilcoxon rank-sum test. Chi-square and Fisher’s exact tests were used for categorical variables, while Poisson and binomial regression models were used to evaluate temporal trends.

RESULTS: Of 2673 tumours analysed, 76% were tested for mismatch repair proteins, with testing rates improving significantly from 58% in 2011 to >99% in 2022. Among these, 14% showed a mismatch repair protein deficiency, with 77% being MLH1-related and 23% non-MLH1-related, categorising them as Lynch-suspected. 73% (n = 257) of the MLH1-deficient tumours underwent further molecular testing for BRAF mutations. Among these, 33% showed no mutation, also categorising them as Lynch-suspected, while the remaining 67% were categorised as sporadic. In total, 6% of the tested tumours were categorised as Lynch-suspected and required further testing and/or genetic counselling. Statistical estimates suggest that among the non-tested tumours, 88 cases could potentially harbour a microsatellite instability, including approximately 5 Lynch-suspected cases. Additionally, in 44 cases, incorrect mismatch repair proteins were tested, potentially leading to missed microsatellite instability. Among the 59 tumours that did not undergo BRAF testing, approximately 20 may have been Lynch-suspected and missed due to insufficient testing. Tumour incidence and the proportion of Lynch-suspected tumours among all tumours remained stable over time, without cantonal hotspots.

CONCLUSIONS: Remarkable progress in colorectal cancer diagnostics across Central Switzerland could be demonstrated, leading to a near-complete compliance with guidelines for mismatch repair proteins and molecular testing by 2022. This high adherence to guidelines provides a solid foundation for better personalised surveillance and treatment, ultimately improving the quality of care for colorectal cancer patients in the region. However, during the early years of the study some gaps existed, particularly in testing practices for rectal cancers and incomplete molecular follow-up, potentially missing some patients with a microsatellite instability, who could have benefited from different therapies, and Lynch syndrome patients, who together with their families could have benefited from tighter surveillance.

References

  1. Valle L, Vilar E, Tavtigian SV, Stoffel EM. Genetic predisposition to colorectal cancer: syndromes, genes, classification of genetic variants and implications for precision medicine. J Pathol. 2019 Apr;247(5):574–88. doi: https://doi.org/10.1002/path.5229
  2. Yurgelun MB, Kulke MH, Fuchs CS, Allen BA, Uno H, Hornick JL, et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol. 2017 Apr;35(10):1086–95. doi: https://doi.org/10.1200/JCO.2016.71.0012
  3. Li GM. Mechanisms and functions of DNA mismatch repair. Cell Res. 2008 Jan;18(1):85–98. doi: https://doi.org/10.1038/cr.2007.115
  4. Castillejo A, Hernández-Illán E, Rodriguez-Soler M, Pérez-Carbonell L, Egoavil C, Barberá VM, et al. Prevalence of MLH1 constitutional epimutations as a cause of Lynch syndrome in unselected versus selected consecutive series of patients with colorectal cancer. J Med Genet. 2015 Jul;52(7):498–502. doi: https://doi.org/10.1136/jmedgenet-2015-103076
  5. Pinto D, Pinto C, Guerra J, Pinheiro M, Santos R, Vedeld HM, et al. Contribution of MLH1 constitutional methylation for Lynch syndrome diagnosis in patients with tumor MLH1 downregulation. Cancer Med. 2018 Feb;7(2):433–44. doi: https://doi.org/10.1002/cam4.1285
  6. Tutlewska K, Lubinski J, Kurzawski G. Germline deletions in the EPCAM gene as a cause of Lynch syndrome - literature review. Hered Cancer Clin Pract. 2013 Aug;11(1):9. doi: https://doi.org/10.1186/1897-4287-11-9
  7. Tariq K, Ghias K. Colorectal cancer carcinogenesis: a review of mechanisms. Cancer Biol Med. 2016 Mar;13(1):120–35. doi: https://doi.org/10.20892/j.issn.2095-3941.2015.0103
  8. Pawlik TM, Raut CP, Rodriguez-Bigas MA. Colorectal carcinogenesis: MSI-H versus MSI-L. Dis Markers. 2004;20(4-5):199–206. doi: https://doi.org/10.1155/2004/368680
  9. Elsayed FA, Kets CM, Ruano D, van den Akker B, Mensenkamp AR, Schrumpf M, et al. Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer. Eur J Hum Genet. 2015 Aug;23(8):1080–4. doi: https://doi.org/10.1038/ejhg.2014.242
  10. Martínez-Roca A, Giner-Calabuig M, Murcia O, Castillejo A, Soto JL, García-Heredia A, et al. Lynch-like Syndrome: Potential Mechanisms and Management. Cancers (Basel). 2022 Feb;14(5):1115. doi: https://doi.org/10.3390/cancers14051115
  11. Rodríguez-Soler M, Pérez-Carbonell L, Guarinos C, Zapater P, Castillejo A, Barberá VM, et al. Risk of cancer in cases of suspected lynch syndrome without germline mutation. Gastroenterology. 2013 May;144(5):926–932.e1. doi: https://doi.org/10.1053/j.gastro.2013.01.044
  12. Win AK, Dowty JG, Reece JC, Lee G, Templeton AS, Plazzer JP, et al.; International Mismatch Repair Consortium. Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study. Lancet Oncol. 2021 Jul;22(7):1014–22. doi: https://doi.org/10.1016/S1470-2045(21)00189-3
  13. Idos G, Valle L. Table 8 [Recommended Surveillance for Individuals with Lynch Syndrome]Seattle: University of Washington; 2021.[Internet][ [cited 2025 Mar 18]], Available from https://www.ncbi.nlm.nih.gov/books/NBK1211/table/hnpcc.T.recommended_surveillance_for_ind/
  14. Seppälä TT, Latchford A, Negoi I, Sampaio Soares A, Jimenez-Rodriguez R, Sánchez-Guillén L, et al.; European Hereditary Tumour Group (EHTG) and European Society of Coloproctology (ESCP). 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 May;108(5):484–98. doi: https://doi.org/10.1002/bjs.11902
  15. Bhattacharya P, Leslie SW, McHugh TW. Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer). StatPearls [Internet]Treasure Island (FL): StatPearls Publishing; 2024.[ [cited 2024 Jun 26]], Available from http://www.ncbi.nlm.nih.gov/books/NBK431096/
  16. Dunne PD, Arends MJ. Molecular pathological classification of colorectal cancer-an update. Virchows Arch. 2024 Feb;484(2):273–85. doi: https://doi.org/10.1007/s00428-024-03746-3
  17. Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015 Jan;5(1):43–51. doi: https://doi.org/10.1158/2159-8290.CD-14-0863
  18. Chang L, Chang M, Chang HM, Chang F. Microsatellite Instability: A Predictive Biomarker for Cancer Immunotherapy. Appl Immunohistochem Mol Morphol. 2018 Feb;26(2):e15–21. doi: https://doi.org/10.1097/PAI.0000000000000575
  19. Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, et al. PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer. N Engl J Med. 2022 Jun;386(25):2363–76. doi: https://doi.org/10.1056/NEJMoa2201445
  20. Qualitaet-Qualitaetsrichtlinien-SGPath_DE_2011.pdf [Internet]. [cited 2024 Nov 12]. Available from: https://www.sgpath.ch/customer/files/231/Qualitaet-Qualitaetsrichtlinien-SGPath_DE_2011.pdf
  21. Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Rüschoff J, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004 Feb;96(4):261–8. doi: https://doi.org/10.1093/jnci/djh034
  22. Qualitaet-QRL-KolonRektum-SGPath-2019.pdf [Internet]. [cited 2024 Nov 12]. Available from: https://www.sgpath.ch/customer/files/231/Qualitaet-QRL-KolonRektum-SGPath-2019.pdf
  23. Organisation [Internet]. Luzerner Kantonsspital. [cited 2024 Aug 9]. Available from: https://www.luks.ch/ihr-luks/organisation
  24. Parsons MT, Buchanan DD, Thompson B, Young JP, Spurdle AB. Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification. J Med Genet. 2012 Mar;49(3):151–7. doi: https://doi.org/10.1136/jmedgenet-2011-100714
  25. Age‐dependent performance of BRAF mutation testing in Lynch syndrome diagnostics - Bläker - 2020 - International Journal of Cancer - Wiley Online Library [Internet]. [cited 2024 Aug 14]. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.33273
  26. Berg KD, Glaser CL, Thompson RE, Hamilton SR, Griffin CA, Eshleman JR. Detection of microsatellite instability by fluorescence multiplex polymerase chain reaction. J Mol Diagn. 2000 Feb;2(1):20–8. doi: https://doi.org/10.1016/S1525-1578(10)60611-3
  27. Statistik B für. Bilanz der ständigen Wohnbevölkerung nach Kanton, 1991-2022 - 1991-2022 | Tabelle [Internet]. Bundesamt für Statistik. 2023 [cited 2024 Aug 9]. Available from: https://www.bfs.admin.ch/asset/de/26565330
  28. Trojan J, Stintzing S, Haase O, Koch C, Ziegler P, Demes M, et al. Complete Pathological Response After Neoadjuvant Short-Course Immunotherapy with Ipilimumab and Nivolumab in Locally Advanced MSI-H/dMMR Rectal Cancer. Oncologist. 2021 Dec;26(12):e2110–4. doi: https://doi.org/10.1002/onco.13955
  29. De Smedt L, Lemahieu J, Palmans S, Govaere O, Tousseyn T, Van Cutsem E, et al. Microsatellite instable vs stable colon carcinomas: analysis of tumour heterogeneity, inflammation and angiogenesis. Br J Cancer. 2015 Jul;113(3):500–9. doi: https://doi.org/10.1038/bjc.2015.213
  30. Vilar E, Gruber SB. Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol. 2010 Mar;7(3):153–62. doi: https://doi.org/10.1038/nrclinonc.2009.237
  31. Ward R, Meagher A, Tomlinson I, O’Connor T, Norrie M, Wu R, et al. Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut. 2001 Jun;48(6):821–9. doi: https://doi.org/10.1136/gut.48.6.821
  32. Martin S, Katainen R, Taira A, Välimäki N, Ristimäki A, Seppälä T, et al. Lynch syndrome-associated and sporadic microsatellite unstable colorectal cancers: different patterns of clonal evolution yield highly similar tumours. Hum Mol Genet. 2024 Nov;33(21):1858–72. doi: https://doi.org/10.1093/hmg/ddae124
  33. Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet. 2009 Jul;76(1):1–18. doi: https://doi.org/10.1111/j.1399-0004.2009.01230.x
  34. Zumstein V, Vinzens F, Zettl A, Heinimann K, Koeberle D, Flüe M von, et al. Systematic immunohistochemical screening for Lynch syndrome in colorectal cancer: a single centre experience of 486 patients. Swiss Med Wkly. 2016 Apr 24;146(1718):w14315–w14315.
  35. Rüschoff J, Schildhaus HU, Rüschoff JH, Jöhrens K, Bocker Edmonston T, Dietmaier W, et al. Testing for deficient mismatch repair and microsatellite instability : A focused update. Pathologie (Heidelb). 2023 Nov;44(S2 Suppl 2):61–70. doi: https://doi.org/10.1007/s00292-023-01208-2
  36. Wang C, Zhang L, Vakiani E, Shia J. Detecting mismatch repair deficiency in solid neoplasms: immunohistochemistry, microsatellite instability, or both? Mod Pathol. 2022 Nov;35(11):1515–28. doi: https://doi.org/10.1038/s41379-022-01109-4