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Dal Buono, A. Microsatellite Instability in Colorectal Cancers. Encyclopedia. Available online: https://encyclopedia.pub/entry/18728 (accessed on 21 July 2024).
Dal Buono A. Microsatellite Instability in Colorectal Cancers. Encyclopedia. Available at: https://encyclopedia.pub/entry/18728. Accessed July 21, 2024.
Dal Buono, Arianna. "Microsatellite Instability in Colorectal Cancers" Encyclopedia, https://encyclopedia.pub/entry/18728 (accessed July 21, 2024).
Dal Buono, A. (2022, January 24). Microsatellite Instability in Colorectal Cancers. In Encyclopedia. https://encyclopedia.pub/entry/18728
Dal Buono, Arianna. "Microsatellite Instability in Colorectal Cancers." Encyclopedia. Web. 24 January, 2022.
Microsatellite Instability in Colorectal Cancers
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This entry is adapted from the peer-reviewed paper 10.3390/jpm11121333

Microsatellite instability (MSI) is the landmark feature of DNA mismatch repair deficiency, which can be found in 15–20% of all colorectal cancers (CRC). 

microsatellite instability colorectal cancer immunotherapy

1. Introduction

Colorectal cancer (CRC) is the third most common malignancy and cause of cancer mortality in Europe and the United States, accounting for nearly 900.000 deaths every year worldwide [1]. Among the newly diagnosed CRC, approximately 20% of patients still present with a metastatic disease, and a further 25% of those with an initially localized disease will eventually develop distant metastases [2][3]. Despite the fact that staging has traditionally represented the backbone of the prognostic factors in oncology, the growing knowledge of the molecular mechanisms of CRC has revolutionized the traditional or “old school” methods of managing tumor conditions. Indeed, CRC is a highly heterogeneous disease in regard to molecular expression and genetic abnormalities. It is known that a small subset of CRCs, approximately 15% of the cases, demonstrate microsatellite instability (MSI) due to an impaired DNA mismatch repair (MMR) system, though the vast majority of CRCs belong to the microsatellite stable (MSS) biomarker list [4]. MSI-CRCs are mostly sporadic, while approximately 3% of all CRCs harbor a germline mutation of mismatch repair genes (i.e., MLH1, MSH2, MSH6, PMS2, and EpCAM) identifying the Lynch syndrome [5]. The understanding of the carcinogenesis of MMR deficient tumors and subsequent clinical research has had an enormous therapeutic impact in the field of gastrointestinal oncology. In particular, the MSI status defines the largest group of inherited predispositions to gastrointestinal cancers and impacts the prognosis of CRC, giving better stage-adjusted survival rates compared to MSS tumors [6][7]. Moreover, MSI colorectal tumors are more frequently seen at early stages (i.e., stage II–III), and only 3.5% of the cases present with a metastatic disease [8], in accordance with a reduced distant metastasis, which is intrinsic to MSI status. MMR/MSI testing is increasingly being incorporated as a standard of care for all CRC patients and is collectively recommended by the most important scientific societies involved in the field, such as AGA, ASGE, ASCRS, ASCO, and ESMO [9].

2. Prognostic Value of MSI in CRC

2.1. Lower Metastatic Potential and Better Survival of MSI CRC

MSI is undoubtedly a positive prognostic factor in CRC patients, which is promptly explained by the low prevalence of MSI tumors among metastatic CRCs, corresponding to 2–4% of stage IV cases [4][10], as compared to their prevalence in earlier stages [11][12]. MSI CRCs typically present a dense immune cell infiltration, particularly rich in TILs, which has been associated with a better prognosis and a reduced tendency to metastasize [8]. Substantial evidence supports that MSI is a strong prognostic marker in early-stage CRCs with a favorable impact on survival, beyond the TNM staging system also from pooled retrospective analyses [13]. With respect to stage II CRC patients, in the ACCENT database analysis, the MSI profile significantly improved the disease-free survival and the overall survival [14].
Compared to stage II, the prognostic value of MSI in stage III CRC is less defined, and contradictory data have emerged from randomized clinical trials (RCTs) and meta-analysis [15][16][17] (see below).
Summarizing the available data, MSI confers a favorable prognosis in stage II CRC, and this effect seems to be progressively reduced with advancing stage (i.e., stage III) [15][16][17]. A speculative explanation of this phenomenon lies in the evasion of immune surveillance that is possibly acquired in more advanced stages of the disease. In accordance with the above statement, in stage IV CRCs, MSI no longer provides an advantage in terms of prognosis [18][19], though interactions with chemotherapy, as the standard adjuvant treatment for stage III CRC, should not be disregarded despite being difficult to disentangle.

2.2. Adaptive Immune Response and the Relevance of Immune Parameters

MSI-CRCs attract a dense lymphocytic infiltrate [20][21], parallelly driving the infiltration of specific subsets of immune cells (i.e., cytotoxic and helper T-lymphocytes) that are associated with an improved prognosis and reduced recurrence rates after surgery [18], especially in patients with early, node-negative CRC, largely contributing to the prognostic advantage of high densities of infiltrating lymphocytes [22].
Among the immune subpopulations recruited by MSI-CRC, dendritic cells and T cells activate the immune antitumoral response, which is downstream accomplished by activated memory CD4 + T cells, NK cells, M1 macrophages, and neutrophils [23]. The attempt to measure the immune infiltrate in the primary tumor and to assess its prognostic value has been pursued by trying to build a reliable “immuno-score” that quantifies the amount of infiltrating T-lymphocytes and allows inferences on CRC outcomes [24]. The immuno-score has been suggested to be superior to the conventional TNM classification in CRC, given its ability to differentiate patients with a better or worse prognosis in MSS and MSI disease, as across the various stages according to AJCC/UICC [25]. The measure of CD8+ cells and CD45RO+ memory cells in specific tumor regions (i.e., at the invasive front) has been, in fact, linked to longer overall survival in MSI-CRC patients [26]. This parameter is likely to be included in the TNM staging, similarly to its use for MSI, although some refinement is necessary in order to better define its reliability in stage III disease [27][28].

References

  1. Biller, L.H.; Schrag, D. Diagnosis and Treatment of Metastatic Colorectal Cancer: A Review. JAMA 2021, 325, 669–685.
  2. Siegel, R.L.; Miller, K.D.; Goding Sauer, A.; Fedewa, S.A.; Butterly, L.F.; Anderson, J.C.; Cercek, A.; Smith, R.A.; Jemal, A. Colorectal cancer statistics, 2020. CA Cancer J. Clin. 2020, 70, 145–164.
  3. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Colorectal Cancer. Available online: https://seer.cancer.gov/statfacts/html/colorect.html (accessed on 9 September 2021).
  4. Boland, C.R.; Goel, A. Microsatellite instability in colorectal cancer. Gastroenterology 2010, 138, 2073–2087.
  5. Ward, R.; Meagher, A.; Tomlinson, I.; O’Connor, T.; Norrie, M.; Wu, R.; Hawkins, N. Microsatellite instability and the clinico-pathological features of sporadic colorectal cancer. Gut 2001, 48, 821–882.
  6. Taieb, J.; Shi, Q.; Pederson, L.; Alberts, S.; Wolmark, N.; Van Cutsem, E.; de Gramont, A.; Kerr, R.; Grothey, A.; Lonardi, S.; et al. Prognosis of microsatellite instability and/or mismatch repair deficiency stage III colon cancer patients after disease recurrence following adjuvant treatment: Results of an ACCENT pooled analysis of seven studies. Ann. Oncol. 2019, 30, 1466–1471.
  7. Jin, Z.; Sinicrope, F.A. Prognostic and Predictive Values of Mismatch Repair Deficiency in Non-Metastatic Colorectal Cancer. Cancers 2021, 13, 300.
  8. Ganesh, K.; Stadler, Z.K.; Cercek, A.; Mendelsohn, R.B.; Shia, J.; Segal, N.H.; Diaz, L.A., Jr. Immunotherapy in colorectal cancer: Rationale, challenges and potential. Nat. Rev. Gastroenterol. Hepatol. 2019, 16, 361–375.
  9. Messersmith, W.A. NCCN Guidelines Updates: Management of Metastatic Colorectal Cancer. J. Natl. Compr. Canc. Net. 2019, 17, 599–601.
  10. Peltomäki, P. Update on Lynch syndrome genomics. Fam. Cancer 2016, 15, 385–393.
  11. Sankila, R.; Aaltonen, L.A.; Järvinen, H.J.; Mecklin, J.P. Better survival rates in patients with MLH1-associated hereditary colorectal cancer. Gastroenterology 1996, 110, 682–687.
  12. Gryfe, R.; Gallinger, S. Microsatellite instability, mismatch repair deficiency, and colorectal cancer. Surgery 2001, 130, 17–20.
  13. Dienstmann, R.; Mason, M.J.; Sinicrope, F.A.; Phipps, A.I.; Tejpar, S.; Nesbakken, A.; Danielsen, S.A.; Sveen, A.; Buchanan, D.D.; Clendenning, M.; et al. Prediction of overall survival in stage II and III colon cancer beyond TNM system: A retrospective, pooled biomarker study. Ann. Oncol. 2017, 28, 1023–1031.
  14. Sargent, D.J.; Shi, Q.; Yothers, G.; Tejpar, S.; Bertagnolli, M.M.; Thibodeau, S.N.; Andre, T.; Labianca, R.; Gallinger, S.; Hamilton, S.R.; et al. Prognostic impact of deficient mismatch repair (dMMR) in 7,803 stage II/III colon cancer (CC) patients (pts): A pooled individual pt data analysis of 17 adjuvant trials in the ACCENT database. J. Clin. Oncol. 2014, 32, 3507.
  15. Klingbiel, D.; Saridaki, Z.; Roth, A.D.; Bosman, F.T.; Delorenzi, M.; Tejpar, S. Prognosis of stage II and III colon cancer treated with adjuvant 5-fluorouracil or FOLFIRI in relation to microsatellite status: Results of the PETACC−3 trial. Ann. Oncol. 2015, 26, 126–132.
  16. Wang, B.; Li, F.; Zhou, X.; Ma, Y.; Fu, W. Is microsatellite instability-high really a favorable prognostic factor for advanced colorectal cancer? A meta-analysis. World J. Surg. Oncol. 2019, 17, 169.
  17. Buckowitz, A.; Knaebel, H.P.; Benner, A.; Blaker, H.; Gebert, J.; Kienle, P.; von Doeberitz, K.M.; Kloor, M. Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases. Br. J. Cancer 2005, 92, 1746–1753.
  18. Venderbosch, S.; Nagtegaal, I.D.; Maughan, T.S.; Smith, C.G.; Cheadle, J.P.; Fisher, D.; Kaplan, R.; Quirke, P.; Seymour, M.T.; Richman, S.D.; et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: A pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin. Cancer Res. 2014, 20, 5322–5330.
  19. Laghi, L.; Bianchi, P.; Miranda, E.; Balladore, E.; Pacetti, V.; Grizzi, F.; Allavena, P.; Torri, V.; Repici, A.; Santoro, A.; et al. CD3+ cells at the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of post-surgical metastasis: A longitudinal study. Lancet Oncol. 2009, 10, 877–884.
  20. Kim, H.; Jen, J.; Vogelstein, B.; Hamilton, S.R. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am. J. Pathol. 1994, 145, 148–156.
  21. Guidoboni, M.; Gafà, R.; Viel, A.; Doglioni, C.; Russo, A.; Santini, A.; Del Tin, L.; Macrì, E.; Lanza, G.; Boiocchi, M.; et al. Microsatellite instability and high content of activated cytotoxic lymphocytes identify colon cancer patients with a favorable prognosis. Am. J. Pathol. 2001, 159, 297–304.
  22. Pagès, F.; Kirilovsky, A.; Mlecnik, B.; Asslaber, M.; Tosolini, M.; Bindea, G.; Galon, J. In situ cytotoxic and memory T cells predict outcome in patients with early stage colorectal cancer. J. Clin. Oncol. 2009, 27, 5944–5951.
  23. Lin, A.; Zhang, J.; Luo, P. Crosstalk Between the MSI Status and Tumor Microenvironment in Colorectal Cancer. Front Immunol. 2020, 11, 2039.
  24. Galon, J.; Mlecnik, B.; Bindea, G.; Angell, H.K.; Berger, A.; Lagorce, C.; Pagès, F. Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours. J. Pathol. 2014, 232, 199–209.
  25. Wirta, E.V.; Seppälä, T.; Friman, M.; Väyrynen, J.; Ahtiainen, M.; Kautiainen, H.; Kuopio, T.; Kellokumpu, I.; Mecklin, J.P.; Böhm, J. Immunoscore in mismatch repair-proficient and -deficient colon cancer. J. Pathol. Clin. Res. 2017, 3, 203–213.
  26. Noepel-Duennebacke, S.; Juette, H.; Schulmann, K.; Graeven, U.; Porschen, R.; Stoehlmacher, J.; Hegewisch-Becker, S.; Raulf, A.; Arnold, D.; Reinacher-Schick, A.; et al. Microsatellite instability (MSI-H) is associated with a high immunoscore but not with PD-L1 expression or increased survival in patients (pts.) with metastatic colorectal cancer (mCRC) treated with oxaliplatin (ox) and fluoropyrimidine (FP) with and without bevacizumab (bev): A pooled analysis of the AIO KRK 0207 and RO91 trials. J. Cancer Res. Clin. Oncol. 2021, 147, 3063–3072.
  27. Laghi, L.; Negri, F.; Gaiani, F.; Cavalleri, T.; Grizzi, F.; De’ Angelis, G.L.; Malesci, A. Prognostic and Predictive Cross-Roads of Microsatellite Instability and Immune Response to Colon Cancer. Int. J. Mol. Sci. 2020, 21, 9680.
  28. Samowitz, W.S.; Albertsen, H.; Herrick, J.; Levin, T.R.; Sweeney, C.; Murtaugh, M.A.; Wolff, R.K.; Slattery, M.L. Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology 2005, 129, 837–845.
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Arianna Dal Buono
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Entry Collection: Gastrointestinal Disease
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Update Date: 25 Jan 2022
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