{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T20:11:06Z","timestamp":1783627866987,"version":"3.55.0"},"reference-count":78,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100005713","name":"Technische Universit\u00e4t M\u00fcnchen","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005713","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Virchows Arch"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Microsatellite instability (MSI), caused by impaired mismatch repair (MMR), has gained prominence as a biomarker predicting response to immune checkpoint inhibitors in various cancers. MSI-high (MSI-H) tumours exhibit widespread instability across multiple microsatellite loci and are well-characterized. In contrast, low-level microsatellite instability (MSI-L)\u2014marked by instability at a low number of loci\u2014is poorly understood and its biological relevance remains controversial. MSI-L has often been grouped together with microsatellite stable (MSS) tumours, given the lack of consistent molecular distinctions. However, some studies, particularly in colorectal and gastric cancers, have reported that MSI-L correlates with distinct clinical and molecular features, including poorer prognosis, increased tumour mutational burden (TMB) following chemotherapy, and better response to platinum\/5-fluorouracil-based neoadjuvant chemotherapy. Notably, these associations frequently involve instability at dinucleotide repeat markers, hinting at a specific subset of MSI-L. Moreover, recent data provide initial evidence that MSI-L may be associated with subtle alterations of genes involved in DNA damage tolerance pathways. This review aims to clarify the current understanding of MSI-L by (a) comparing diagnostic methods and their influence on MSI-L classification, (b) summarizing clinical and molecular associations of MSI-L specifically in gastric and colorectal cancer, (c) highlighting new aspects regarding potential mechanisms underlying MSI-L, focusing on the particular unstable marker and a possible role of the DNA damage tolerance pathways, and (d) discussing whether MSI-L, particularly defined by dinucleotide repeat instability, may serve as a marker for therapeutic vulnerability.<\/jats:p>","DOI":"10.1007\/s00428-026-04400-w","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T16:58:50Z","timestamp":1769014730000},"page":"215-228","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Low microsatellite instability revisited: a review"],"prefix":"10.1007","volume":"488","author":[{"given":"Bianca","family":"Grosser","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meike","family":"Kohlruss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2886-0371","authenticated-orcid":false,"given":"Gisela","family":"Keller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,21]]},"reference":[{"key":"4400_CR1","doi-asserted-by":"publisher","first-page":"2509","DOI":"10.1056\/NEJMoa1500596","volume":"372","author":"DT Le","year":"2015","unstructured":"Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD et al (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509\u20132520. https:\/\/doi.org\/10.1056\/NEJMoa1500596","journal-title":"N Engl J Med"},{"key":"4400_CR2","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1126\/science.aan6733","volume":"357","author":"DT Le","year":"2017","unstructured":"Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK et al (2017) Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357:409\u2013413. https:\/\/doi.org\/10.1126\/science.aan6733","journal-title":"Science"},{"key":"4400_CR3","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1016\/s0002-9440(10)64020-5","volume":"158","author":"JR Jass","year":"2001","unstructured":"Jass JR, Young J, Leggett BA (2001) Biological significance of microsatellite instability-low (MSI-L) status in colorectal tumors. Am J Pathol 158:779\u2013781. https:\/\/doi.org\/10.1016\/s0002-9440(10)64020-5","journal-title":"Am J Pathol"},{"key":"4400_CR4","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1002\/path.1071","volume":"197","author":"I Tomlinson","year":"2002","unstructured":"Tomlinson I, Halford S, Aaltonen L, Hawkins N, Ward R (2002) Does MSI-low exist? J Pathol 197:6\u201313. https:\/\/doi.org\/10.1002\/path.1071","journal-title":"J Pathol"},{"key":"4400_CR5","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1155\/2004\/368680","volume":"20","author":"TM Pawlik","year":"2004","unstructured":"Pawlik TM, Raut CP, Rodriguez-Bigas MA (2004) Colorectal carcinogenesis: MSI-H versus MSI-L. Dis Markers 20:199\u2013206. https:\/\/doi.org\/10.1155\/2004\/368680","journal-title":"Dis Markers"},{"key":"4400_CR6","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1038\/nature13480","volume":"513","author":"Cancer Genome Atlas Research N","year":"2014","unstructured":"Cancer Genome Atlas Research N (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513:202\u2013209. https:\/\/doi.org\/10.1038\/nature13480","journal-title":"Nature"},{"key":"4400_CR7","doi-asserted-by":"publisher","first-page":"1342","DOI":"10.1038\/nm.4191","volume":"22","author":"RJ Hause","year":"2016","unstructured":"Hause RJ, Pritchard CC, Shendure J, Salipante SJ (2016) Classification and characterization of microsatellite instability across 18 cancer types. Nat Med 22:1342\u20131350. https:\/\/doi.org\/10.1038\/nm.4191","journal-title":"Nat Med"},{"key":"4400_CR8","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1002\/ijc.29449","volume":"137","author":"SY Kim","year":"2015","unstructured":"Kim SY, Choi YY, An JY, Shin HB, Jo A, Choi H et al (2015) The benefit of microsatellite instability is attenuated by chemotherapy in stage II and stage III gastric cancer: results from a large cohort with subgroup analyses. Int J Cancer 137:819\u2013825. https:\/\/doi.org\/10.1002\/ijc.29449","journal-title":"Int J Cancer"},{"key":"4400_CR9","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/s1525-1578(10)60611-3","volume":"2","author":"KD Berg","year":"2000","unstructured":"Berg KD, Glaser CL, Thompson RE, Hamilton SR, Griffin CA, Eshleman JR (2000) Detection of microsatellite instability by fluorescence multiplex polymerase chain reaction. J Mol Diagn 2:20\u201328. https:\/\/doi.org\/10.1016\/s1525-1578(10)60611-3","journal-title":"J Mol Diagn"},{"key":"4400_CR10","first-page":"5248","volume":"58","author":"CR Boland","year":"1998","unstructured":"Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW et al (1998) A national cancer institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58:5248\u20135257","journal-title":"Cancer Res"},{"key":"4400_CR11","doi-asserted-by":"publisher","first-page":"2073","DOI":"10.1053\/j.gastro.2009.12.064","volume":"138","author":"CR Boland","year":"2010","unstructured":"Boland CR, Goel A (2010) Microsatellite instability in colorectal cancer. Gastroenterology 138:2073-2087 e2073. https:\/\/doi.org\/10.1053\/j.gastro.2009.12.064","journal-title":"Gastroenterology"},{"key":"4400_CR12","first-page":"4749","volume":"57","author":"W Dietmaier","year":"1997","unstructured":"Dietmaier W, Wallinger S, Bocker T, Kullmann F, Fishel R, Ruschoff J (1997) Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Res 57:4749\u20134756","journal-title":"Cancer Res"},{"key":"4400_CR13","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1093\/jnci\/djh034","volume":"96","author":"A Umar","year":"2004","unstructured":"Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Ruschoff J et al (2004) Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261\u2013268.\u00a0https:\/\/doi.org\/10.1093\/jnci\/djh034","journal-title":"J Natl Cancer Inst"},{"key":"4400_CR14","doi-asserted-by":"publisher","unstructured":"Dietmaier W, Hirsch D, Ruschoff J (2025) [Microsatellite instability-What should be considered in routine examinations?]. Pathologie (Heidelb) 46:122\u2013125. https:\/\/doi.org\/10.1007\/s00292-024-01392-9","DOI":"10.1007\/s00292-024-01392-9"},{"key":"4400_CR15","doi-asserted-by":"publisher","first-page":"305","DOI":"10.2353\/jmoldx.2006.050092","volume":"8","author":"KM Murphy","year":"2006","unstructured":"Murphy KM, Zhang S, Geiger T, Hafez MJ, Bacher J, Berg KD et al (2006) Comparison of the microsatellite instability analysis system and the Bethesda-Panel for the determination of microsatellite instability in colorectal cancers. J Mol Diagn 8:305\u2013311. https:\/\/doi.org\/10.2353\/jmoldx.2006.050092\u00a0","journal-title":"J Mol Diagn"},{"key":"4400_CR16","doi-asserted-by":"publisher","unstructured":"Xicola RM, Llor X, Pons E, Castells A, Alenda C, Pinol V et al (2007) Performance of different microsatellite marker panels for detection of mismatch repair-deficient colorectal tumors. J Natl Cancer Inst 99:244\u2013252. https:\/\/doi.org\/10.1093\/jnci\/djk033","DOI":"10.1093\/jnci\/djk033"},{"key":"4400_CR17","doi-asserted-by":"publisher","unstructured":"Suraweera N, Duval A, Reperant M, Vaury C, Furlan D, Leroy K et al (2002) Evaluation of tumor microsatellite instability using five quasimonomorphic mononucleotide repeats and pentaplex PCR. Gastroenterology 123:1804\u20131811. https:\/\/doi.org\/10.1053\/gast.2002.37070","DOI":"10.1053\/gast.2002.37070"},{"key":"4400_CR18","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1111\/his.14271","volume":"78","author":"J Shia","year":"2021","unstructured":"Shia J (2021) The diversity of tumours with microsatellite instability: molecular mechanisms and impact upon microsatellite instability testing and mismatch repair protein immunohistochemistry. Histopathology 78:485\u2013497. https:\/\/doi.org\/10.1111\/his.14271","journal-title":"Histopathology"},{"key":"4400_CR19","doi-asserted-by":"publisher","first-page":"1515","DOI":"10.1038\/s41379-022-01109-4","volume":"35","author":"C Wang","year":"2022","unstructured":"Wang C, Zhang L, Vakiani E, Shia J (2022) Detecting mismatch repair deficiency in solid neoplasms: immunohistochemistry, microsatellite instability, or both? Mod Pathol 35:1515\u20131528. https:\/\/doi.org\/10.1038\/s41379-022-01109-4","journal-title":"Mod Pathol"},{"key":"4400_CR20","doi-asserted-by":"publisher","unstructured":"Wang Y, Shi C, Eisenberg R, Vnencak-Jones CL (2017) Differences in microsatellite instability profiles betweenen dometrioid and colorectal cancers: a potential cause for false-negative results? J Mol Diagn 19:57\u201364. https:\/\/doi.org\/10.1016\/j.jmoldx.2016.07.008","DOI":"10.1016\/j.jmoldx.2016.07.008"},{"key":"4400_CR21","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1038\/s41379-021-00918-3","volume":"35","author":"M Jaffrelot","year":"2022","unstructured":"Jaffrelot M, Fares N, Brunac AC, Laurenty AP, Danjoux M, Grand D et al (2022) An unusual phenotype occurs in 15% of mismatch repair-deficient tumors and is associated with non-colorectal cancers and genetic syndromes. Mod Pathol 35:427\u2013437. https:\/\/doi.org\/10.1038\/s41379-021-00918-3","journal-title":"Mod Pathol"},{"key":"4400_CR22","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1016\/j.jmoldx.2023.07.003","volume":"25","author":"JW Bacher","year":"2023","unstructured":"Bacher JW, Udho EB, Strauss EE, Vyazunova I, Gallinger S, Buchanan DD et al (2023) A highly sensitive pan-cancer test for microsatellite instability. J Mol Diagn 25:806\u2013826. https:\/\/doi.org\/10.1016\/j.jmoldx.2023.07.003","journal-title":"J Mol Diagn"},{"key":"4400_CR23","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1016\/j.jmoldx.2019.12.002","volume":"22","author":"K Zwaenepoel","year":"2020","unstructured":"Zwaenepoel K, Holmgaard Duelund J, De Winne K, Maes V, Weyn C, Lambin S et al (2020) Clinical performance of the Idylla MSI test for a rapid assessment of the DNA microsatellite status in human colorectal cancer. J Mol Diagn 22:386\u2013395. https:\/\/doi.org\/10.1016\/j.jmoldx.2019.12.002","journal-title":"J Mol Diagn"},{"key":"4400_CR24","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1007\/s00428-021-03082-w","volume":"479","author":"I Ukkola","year":"2021","unstructured":"Ukkola I, Nummela P, Pasanen A, Kero M, Lepisto A, Kytola S et al (2021) Detection of microsatellite instability with Idylla MSI assay in colorectal and endometrial cancer. Virchows Arch 479:471\u2013479. https:\/\/doi.org\/10.1007\/s00428-021-03082-w","journal-title":"Virchows Arch"},{"key":"4400_CR25","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13061268","volume":"13","author":"J Siemanowski","year":"2021","unstructured":"Siemanowski J, Schomig-Markiefka B, Buhl T, Haak A, Siebolts U, Dietmaier W et al (2021) Managing difficulties of microsatellite instability testing in endometrial cancer-limitations and advantages of four different PCR-based approaches. Cancers (Basel) 13:1268. https:\/\/doi.org\/10.3390\/cancers13061268","journal-title":"Cancers (Basel)"},{"key":"4400_CR26","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1373\/clinchem.2014.223677","volume":"60","author":"SJ Salipante","year":"2014","unstructured":"Salipante SJ, Scroggins SM, Hampel HL, Turner EH, Pritchard CC (2014) Microsatellite instability detection by next generation sequencing. Clin Chem 60:1192\u20131199. https:\/\/doi.org\/10.1373\/clinchem.2014.223677","journal-title":"Clin Chem"},{"key":"4400_CR27","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1093\/bioinformatics\/btt755","volume":"30","author":"B Niu","year":"2014","unstructured":"Niu B, Ye K, Zhang Q, Lu C, Xie M, McLellan MD et al (2014) MSIsensor: microsatellite instability detection using paired tumor-normal sequence data. Bioinformatics 30:1015\u20131016. https:\/\/doi.org\/10.1093\/bioinformatics\/btt755","journal-title":"Bioinformatics"},{"key":"4400_CR28","doi-asserted-by":"publisher","first-page":"7452","DOI":"10.18632\/oncotarget.13918","volume":"8","author":"EA Kautto","year":"2017","unstructured":"Kautto EA, Bonneville R, Miya J, Yu L, Krook MA, Reeser JW et al (2017) Performance evaluation for rapid detection of pan-cancer microsatellite instability with MANTIS. Oncotarget 8:7452\u20137463. https:\/\/doi.org\/10.18632\/oncotarget.13918","journal-title":"Oncotarget"},{"key":"4400_CR29","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00621","volume":"8","author":"LG Baudrin","year":"2018","unstructured":"Baudrin LG, Deleuze JF, How-Kit A (2018) Molecular and computational methods for the detection of microsatellite instability in cancer. Front Oncol 8:621. https:\/\/doi.org\/10.3389\/fonc.2018.00621","journal-title":"Front Oncol"},{"key":"4400_CR30","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1007\/s00292-023-01208-2","volume":"44","author":"J Ruschoff","year":"2023","unstructured":"Ruschoff J, Schildhaus HU, Ruschoff JH, Johrens K, Bocker Edmonston T, Dietmaier W et al (2023) Testing for deficient mismatch repair and microsatellite instability\u202f: a focused update. Pathologe 44:61\u201370. https:\/\/doi.org\/10.1007\/s00292-023-01208-2","journal-title":"Pathologe"},{"key":"4400_CR31","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1007\/s00384-011-1408-0","volume":"27","author":"J Plaschke","year":"2012","unstructured":"Plaschke J, Preussler M, Ziegler A, Schackert HK (2012) Aberrant protein expression and frequent allelic loss of MSH3 in colorectal cancer with low-level microsatellite instability. Int J Colorectal Dis 27:911\u2013919. https:\/\/doi.org\/10.1007\/s00384-011-1408-0","journal-title":"Int J Colorectal Dis"},{"key":"4400_CR32","doi-asserted-by":"publisher","first-page":"8465","DOI":"10.1158\/0008-5472.CAN-08-0002","volume":"68","author":"AC Haugen","year":"2008","unstructured":"Haugen AC, Goel A, Yamada K, Marra G, Nguyen TP, Nagasaka T et al (2008) Genetic instability caused by loss of MutS homologue 3 in human colorectal cancer. Cancer Res 68:8465\u20138472. https:\/\/doi.org\/10.1158\/0008-5472.CAN-08-0002","journal-title":"Cancer Res"},{"key":"4400_CR33","doi-asserted-by":"publisher","unstructured":"Herz AL, Wisser S, Kohlruss M, Slotta-Huspenina J, Jesinghaus M, Grosser B et al (2022) Elevated microsatellite instability at selected tetranucleotide (EMAST) repeats in gastric cancer: a distinct microsatellite instability type with potential clinical impact? J Pathol Clin Res 8: 233\u2013244. https:\/\/doi.org:https:\/\/doi.org\/10.1002\/cjp2.257","DOI":"10.1002\/cjp2.257"},{"key":"4400_CR34","first-page":"1713","volume":"58","author":"SN Thibodeau","year":"1998","unstructured":"Thibodeau SN, French AJ, Cunningham JM, Tester D, Burgart LJ, Roche PC et al (1998) Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res 58:1713\u20131718","journal-title":"Cancer Res"},{"key":"4400_CR35","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1136\/gut.42.5.673","volume":"42","author":"JR Jass","year":"1998","unstructured":"Jass JR, Do KA, Simms LA, Iino H, Wynter C, Pillay SP et al (1998) Morphology of sporadic colorectal cancer with DNA replication errors. Gut 42:673\u2013679. https:\/\/doi.org\/10.1136\/gut.42.5.673","journal-title":"Gut"},{"key":"4400_CR36","first-page":"53","volume":"62","author":"S Halford","year":"2002","unstructured":"Halford S, Sasieni P, Rowan A, Wasan H, Bodmer W, Talbot I et al (2002) Low-level microsatellite instability occurs in most colorectal cancers and is a nonrandomly distributed quantitative trait. Cancer Res 62:53\u201357","journal-title":"Cancer Res"},{"key":"4400_CR37","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1002\/path.1453","volume":"201","author":"SE Halford","year":"2003","unstructured":"Halford SE, Sawyer EJ, Lambros MB, Gorman P, Macdonald ND, Talbot IC et al (2003) MSI-low, a real phenomenon which varies in frequency among cancer types. J Pathol 201:389\u2013394. https:\/\/doi.org\/10.1002\/path.1453","journal-title":"J Pathol"},{"key":"4400_CR38","first-page":"1166","volume":"62","author":"P Laiho","year":"2002","unstructured":"Laiho P, Launonen V, Lahermo P, Esteller M, Guo M, Herman JG et al (2002) Low-level microsatellite instability in most colorectal carcinomas. Cancer Res 62:1166\u20131170","journal-title":"Cancer Res"},{"key":"4400_CR39","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1002\/ijc.26399","volume":"131","author":"JY An","year":"2012","unstructured":"An JY, Kim H, Cheong JH, Hyung WJ, Kim H, Noh SH (2012) Microsatellite instability in sporadic gastric cancer: its prognostic role and guidance for 5-FU based chemotherapy after R0 resection. Int J Cancer 131:505\u2013511. https:\/\/doi.org\/10.1002\/ijc.26399","journal-title":"Int J Cancer"},{"key":"4400_CR40","doi-asserted-by":"publisher","first-page":"1689","DOI":"10.1002\/ijc.29916","volume":"138","author":"R Sugimoto","year":"2016","unstructured":"Sugimoto R, Sugai T, Habano W, Endoh M, Eizuka M, Yamamoto E et al (2016) Clinicopathological and molecular alterations in early gastric cancers with the microsatellite instability-high phenotype. Int J Cancer 138:1689\u20131697. https:\/\/doi.org\/10.1002\/ijc.29916","journal-title":"Int J Cancer"},{"key":"4400_CR41","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1016\/j.cell.2013.10.015","volume":"155","author":"TM Kim","year":"2013","unstructured":"Kim TM, Laird PW, Park PJ (2013) The landscape of microsatellite instability in colorectal and endometrial cancer genomes. Cell 155:858\u2013868. https:\/\/doi.org\/10.1016\/j.cell.2013.10.015","journal-title":"Cell"},{"key":"4400_CR42","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15180","volume":"8","author":"I Cortes-Ciriano","year":"2017","unstructured":"Cortes-Ciriano I, Lee S, Park WY, Kim TM, Park PJ (2017) A molecular portrait of microsatellite instability across multiple cancers. Nat Commun 8:15180. https:\/\/doi.org\/10.1038\/ncomms15180","journal-title":"Nat Commun"},{"key":"4400_CR43","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1136\/gut.48.6.821","volume":"48","author":"R Ward","year":"2001","unstructured":"Ward R, Meagher A, Tomlinson I, O\u2019Connor T, Norrie M, Wu R et al (2001) Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut 48:821\u2013829. https:\/\/doi.org\/10.1136\/gut.48.6.821","journal-title":"Gut"},{"key":"4400_CR44","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1007\/s00384-011-1133-8","volume":"26","author":"C Azzoni","year":"2011","unstructured":"Azzoni C, Bottarelli L, Cecchini S, Silini EM, Bordi C, Sarli L (2011) Sporadic colorectal carcinomas with low-level microsatellite instability: a distinct subgroup with specific clinicopathological and molecular features. Int J Colorectal Dis 26:445\u2013453. https:\/\/doi.org\/10.1007\/s00384-011-1133-8","journal-title":"Int J Colorectal Dis"},{"key":"4400_CR45","doi-asserted-by":"publisher","unstructured":"Kets CM, Hoogerbrugge N, Bodmer D, Willems R, Brunner HG, van Krieken JH et al (2006) Unfavorable pathological characteristics in familial colorectal cancer with low-level microsatellite instability. Mod Pathol 19: 1624\u20131630. https:\/\/doi.org:https:\/\/doi.org\/10.1038\/modpathol.3800701","DOI":"10.1038\/modpathol.3800701"},{"key":"4400_CR46","doi-asserted-by":"publisher","first-page":"2318","DOI":"10.1200\/JCO.2005.00.109","volume":"23","author":"MR Kohonen-Corish","year":"2005","unstructured":"Kohonen-Corish MR, Daniel JJ, Chan C, Lin BP, Kwun SY, Dent OF et al (2005) Low microsatellite instability is associated with poor prognosis in stage C colon cancer. J Clin Oncol 23:2318\u20132324. https:\/\/doi.org\/10.1200\/JCO.2005.00.109","journal-title":"J Clin Oncol"},{"key":"4400_CR47","first-page":"2225","volume":"60","author":"YR Parc","year":"2000","unstructured":"Parc YR, Halling KC, Wang L, Christensen ER, Cunningham JM, French AJ et al (2000) HMSH6 alterations in patients with microsatellite instability-low colorectal cancer. Cancer Res 60:2225\u20132231","journal-title":"Cancer Res"},{"key":"4400_CR48","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.1093\/annonc\/mdz116","volume":"30","author":"C Luchini","year":"2019","unstructured":"Luchini C, Bibeau F, Ligtenberg MJL, Singh N, Nottegar A, Bosse T et al (2019) ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1\/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol 30:1232\u20131243. https:\/\/doi.org\/10.1093\/annonc\/mdz116","journal-title":"Ann Oncol"},{"key":"4400_CR49","doi-asserted-by":"publisher","unstructured":"Bonneville R, Krook MA, Kautto EA, Miya J, Wing MR, Chen HZ et al (2017) Landscape of microsatellite instability across 39 cancer types. JCO Precis Oncol 2017. https:\/\/doi.org:https:\/\/doi.org\/10.1200\/PO.17.00073","DOI":"10.1200\/PO.17.00073"},{"key":"4400_CR50","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1002\/cjp2.137","volume":"5","author":"M Kohlruss","year":"2019","unstructured":"Kohlruss M, Grosser B, Krenauer M, Slotta-Huspenina J, Jesinghaus M, Blank S et al (2019) Prognostic implication of molecular subtypes and response to neoadjuvant chemotherapy in 760 gastric carcinomas: role of Epstein-Barr virus infection and high- and low-microsatellite instability. J Pathol Clin Res 5:227\u2013239. https:\/\/doi.org\/10.1002\/cjp2.137","journal-title":"J Pathol Clin Res"},{"key":"4400_CR51","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1136\/gut.2003.034579","volume":"54","author":"CM Wright","year":"2005","unstructured":"Wright CM, Dent OF, Newland RC, Barker M, Chapuis PH, Bokey EL et al (2005) Low level microsatellite instability may be associated with reduced cancer specific survival in sporadic stage C colorectal carcinoma. Gut 54:103\u2013108. https:\/\/doi.org\/10.1136\/gut.2003.034579","journal-title":"Gut"},{"key":"4400_CR52","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1097\/01.coc.0000221428.35366.cb","volume":"29","author":"S Oliart","year":"2006","unstructured":"Oliart S, Martinez-Santos C, Moreno-Azcoita M, Cerquella C, Nejda N, Daimiel L et al (2006) Do MSI-L sporadic colorectal tumors develop through \u201cmild mutator pathway\u201d? Am J Clin Oncol 29:364\u2013370. https:\/\/doi.org\/10.1097\/01.coc.0000221428.35366.cb","journal-title":"Am J Clin Oncol"},{"key":"4400_CR53","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000002260","volume":"94","author":"SY Lee","year":"2015","unstructured":"Lee SY, Kim DW, Lee HS, Ihn MH, Oh HK, Min BS et al (2015) Low-Level Microsatellite Instability as a Potential Prognostic Factor in Sporadic Colorectal Cancer. Medicine (Baltimore) 94:e2260. https:\/\/doi.org\/10.1097\/MD.0000000000002260","journal-title":"Medicine (Baltimore)"},{"key":"4400_CR54","doi-asserted-by":"publisher","unstructured":"Nazemalhosseini Mojarad E, Kashfi SM, Mirtalebi H, Taleghani MY, Azimzadeh P, Savabkar S et al (2016) Low level of microsatellite instability correlates with poor clinical prognosis in stage II colorectal cancer patients. J Oncol 2016: 2196703. https:\/\/doi.org:https:\/\/doi.org\/10.1155\/2016\/2196703","DOI":"10.1155\/2016\/2196703"},{"key":"4400_CR55","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1093\/carcin\/bgp017","volume":"30","author":"S Asaka","year":"2009","unstructured":"Asaka S, Arai Y, Nishimura Y, Yamaguchi K, Ishikubo T, Yatsuoka T et al (2009) Microsatellite instability-low colorectal cancer acquires a KRAS mutation during the progression from Dukes\u2019 A to Dukes\u2019 B. Carcinogenesis 30:494\u2013499. https:\/\/doi.org\/10.1093\/carcin\/bgp017","journal-title":"Carcinogenesis"},{"key":"4400_CR56","doi-asserted-by":"publisher","first-page":"17727","DOI":"10.1007\/s00432-023-05430-6","volume":"149","author":"M Kohlruss","year":"2023","unstructured":"Kohlruss M, Chakraborty S, Hapfelmeier A, Jesinghaus M, Slotta-Huspenina J, Novotny A et al (2023) Low microsatellite instability: a distinct instability type in gastric cancer? J Cancer Res Clin Oncol 149:17727\u201317737. https:\/\/doi.org\/10.1007\/s00432-023-05430-6","journal-title":"J Cancer Res Clin Oncol"},{"key":"4400_CR57","doi-asserted-by":"publisher","first-page":"1260","DOI":"10.1002\/ijc.33322","volume":"148","author":"Y Imamura","year":"2021","unstructured":"Imamura Y, Toihata T, Haraguchi I, Ogata Y, Takamatsu M, Kuchiba A et al (2021) Immunogenic characteristics of microsatellite instability-low esophagogastric junction adenocarcinoma based on clinicopathological, molecular, immunological and survival analyses. Int J Cancer 148:1260\u20131275. https:\/\/doi.org\/10.1002\/ijc.33322","journal-title":"Int J Cancer"},{"key":"4400_CR58","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1002\/jso.21239","volume":"99","author":"YH Kim","year":"2009","unstructured":"Kim YH, Min BH, Choi HK, Kim SJ, Kim KM, Kim JY et al (2009) Sporadic colorectal carcinomas with low-level microsatellite instability in Korea: do they form a distinct subgroup with distinguished clinicopathological features? J Surg Oncol 99:351\u2013355. https:\/\/doi.org\/10.1002\/jso.21239","journal-title":"J Surg Oncol"},{"key":"4400_CR59","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1007\/s00384-002-0460-1","volume":"18","author":"Z Rudzki","year":"2003","unstructured":"Rudzki Z, Zazula M, Okon K, Stachura J (2003) Low-level microsatellite instability colorectal carcinomas: do they really belong to a \u201cgray zone\u201d between high-level microsatellite instability and microsatellite-stable cancers? Int J Colorectal Dis 18:216\u2013221. https:\/\/doi.org\/10.1007\/s00384-002-0460-1","journal-title":"Int J Colorectal Dis"},{"key":"4400_CR60","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1097\/SLA.0000000000003051","volume":"271","author":"S Hasan","year":"2020","unstructured":"Hasan S, Renz P, Wegner RE, Finley G, Raj M, Monga D et al (2020) Microsatellite instability (MSI) as an independent predictor of pathologic complete response (PCR) in locally advanced rectal cancer: a National Cancer Database (NCDB) analysis. Ann Surg 271:716\u2013723. https:\/\/doi.org\/10.1097\/SLA.0000000000003051","journal-title":"Ann Surg"},{"key":"4400_CR61","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1136\/gut.48.3.360","volume":"48","author":"JM Michael-Robinson","year":"2001","unstructured":"Michael-Robinson JM, Biemer-Huttmann A, Purdie DM, Walsh MD, Simms LA, Biden KG et al (2001) Tumour infiltrating lymphocytes and apoptosis are independent features in colorectal cancer stratified according to microsatellite instability status. Gut 48:360\u2013366. https:\/\/doi.org\/10.1136\/gut.48.3.360","journal-title":"Gut"},{"key":"4400_CR62","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1136\/jcp.52.6.455","volume":"52","author":"JR Jass","year":"1999","unstructured":"Jass JR, Biden KG, Cummings MC, Simms LA, Walsh M, Schoch E et al (1999) Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways. J Clin Pathol 52:455\u2013460. https:\/\/doi.org\/10.1136\/jcp.52.6.455","journal-title":"J Clin Pathol"},{"key":"4400_CR63","first-page":"7743","volume":"61","author":"T Kambara","year":"2001","unstructured":"Kambara T, Matsubara N, Nakagawa H, Notohara K, Nagasaka T, Yoshino T et al (2001) High frequency of low-level microsatellite instability in early colorectal cancer. Cancer Res 61:7743\u20137746","journal-title":"Cancer Res"},{"key":"4400_CR64","first-page":"827","volume":"61","author":"VL Whitehall","year":"2001","unstructured":"Whitehall VL, Walsh MD, Young J, Leggett BA, Jass JR (2001) Methylation of O-6-methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with low-level DNA microsatellite instability. Cancer Res 61:827\u2013830","journal-title":"Cancer Res"},{"key":"4400_CR65","first-page":"4577","volume":"63","author":"Y Mori","year":"2003","unstructured":"Mori Y, Selaru FM, Sato F, Yin J, Simms LA, Xu Y et al (2003) The impact of microsatellite instability on the molecular phenotype of colorectal tumors. Cancer Res 63:4577\u20134582","journal-title":"Cancer Res"},{"key":"4400_CR66","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12061689","author":"B Grosser","year":"2020","unstructured":"Grosser B, Kohlruss M, Slotta-Huspenina J, Jesinghaus M, Pfarr N, Steiger K et al (2020) Impact of tumor localization and molecular subtypes on the prognostic and predictive significance of p53 expression in gastric cancer. Cancers (Basel). https:\/\/doi.org\/10.3390\/cancers12061689","journal-title":"Cancers (Basel)"},{"key":"4400_CR67","doi-asserted-by":"publisher","first-page":"1198","DOI":"10.1136\/jmg-2023-109341","volume":"60","author":"MC Villy","year":"2023","unstructured":"Villy MC, Masliah-Planchon J, Schnitzler A, Delhomelle H, Buecher B, Filser M et al (2023) MSH3: a confirmed predisposing gene for adenomatous polyposis. J Med Genet 60:1198\u20131205. https:\/\/doi.org\/10.1136\/jmg-2023-109341","journal-title":"J Med Genet"},{"key":"4400_CR68","doi-asserted-by":"publisher","first-page":"185","DOI":"10.3390\/genes6020185","volume":"6","author":"JM Carethers","year":"2015","unstructured":"Carethers JM, Koi M, Tseng-Rogenski SS (2015) EMAST is a form of microsatellite instability that is initiated by inflammation and modulates colorectal cancer progression. Genes 6:185\u2013205. https:\/\/doi.org\/10.3390\/genes6020185","journal-title":"Genes"},{"key":"4400_CR69","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1038\/nrg1348","volume":"5","author":"H Ellegren","year":"2004","unstructured":"Ellegren H (2004) Microsatellites: simple sequences with complex evolution. Nat Rev Genet 5:435\u2013445. https:\/\/doi.org\/10.1038\/nrg1348","journal-title":"Nat Rev Genet"},{"key":"4400_CR70","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.mrfmmm.2012.11.003","volume":"743","author":"SE Hile","year":"2013","unstructured":"Hile SE, Shabashev S, Eckert KA (2013) Tumor-specific microsatellite instability: do distinct mechanisms underlie the MSI-L and EMAST phenotypes? Mutat Res 743:67\u201377. https:\/\/doi.org\/10.1016\/j.mrfmmm.2012.11.003","journal-title":"Mutat Res"},{"key":"4400_CR71","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1158\/0008-5472.CAN-09-3049","volume":"70","author":"SN Shah","year":"2010","unstructured":"Shah SN, Hile SE, Eckert KA (2010) Defective mismatch repair, microsatellite mutation bias, and variability in clinical cancer phenotypes. Cancer Res 70:431\u2013435. https:\/\/doi.org\/10.1158\/0008-5472.CAN-09-3049","journal-title":"Cancer Res"},{"key":"4400_CR72","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1038\/s41580-020-0257-5","volume":"21","author":"M Berti","year":"2020","unstructured":"Berti M, Cortez D, Lopes M (2020) The plasticity of DNA replication forks in response to clinically relevant genotoxic stress. Nat Rev Mol Cell Biol 21:633\u2013651. https:\/\/doi.org\/10.1038\/s41580-020-0257-5","journal-title":"Nat Rev Mol Cell Biol"},{"key":"4400_CR73","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1038\/s41568-022-00518-6","volume":"23","author":"E Cybulla","year":"2023","unstructured":"Cybulla E, Vindigni A (2023) Leveraging the replication stress response to optimize cancer therapy. Nat Rev Cancer 23:6\u201324. https:\/\/doi.org\/10.1038\/s41568-022-00518-6","journal-title":"Nat Rev Cancer"},{"key":"4400_CR74","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1016\/j.molcel.2021.01.012","volume":"81","author":"A Quinet","year":"2021","unstructured":"Quinet A, Tirman S, Cybulla E, Meroni A, Vindigni A (2021) To skip or not to skip: choosing repriming to tolerate DNA damage. Mol Cell 81:649\u2013658. https:\/\/doi.org\/10.1016\/j.molcel.2021.01.012","journal-title":"Mol Cell"},{"key":"4400_CR75","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1038\/s41588-025-02152-y","volume":"57","author":"GCC Koh","year":"2025","unstructured":"Koh GCC, Nanda AS, Rinaldi G, Boushaki S, Degasperi A, Badja C et al (2025) A redefined InDel taxonomy provides insights into mutational signatures. Nat Genet 57:1132\u20131141. https:\/\/doi.org\/10.1038\/s41588-025-02152-y","journal-title":"Nat Genet"},{"key":"4400_CR76","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1097\/SLA.0b013e318216f449","volume":"253","author":"K Becker","year":"2011","unstructured":"Becker K, Langer R, Reim D, Novotny A, Meyer zum Buschenfelde C, Engel J et al (2011) Significance of histopathological tumor regression after neoadjuvant chemotherapy in gastric adenocarcinomas: a summary of 480 cases. Ann Surg 253:934\u2013939. https:\/\/doi.org\/10.1097\/SLA.0b013e318216f449","journal-title":"Ann Surg"},{"key":"4400_CR77","doi-asserted-by":"publisher","first-page":"13128","DOI":"10.1002\/jcp.27983","volume":"234","author":"A Torshizi Esfahani","year":"2019","unstructured":"Torshizi Esfahani A, Seyedna SY, Nazemalhosseini Mojarad E, Majd A, Asadzadeh Aghdaei H (2019) MSI-L\/EMAST is a predictive biomarker for metastasis in colorectal cancer patients. J Cell Physiol 234:13128\u201313136. https:\/\/doi.org\/10.1002\/jcp.27983","journal-title":"J Cell Physiol"},{"key":"4400_CR78","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.1046\/j.1365-2168.1998.00940.x","volume":"85","author":"JR Siewert","year":"1998","unstructured":"Siewert JR, Stein HJ (1998) Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg 85:1457\u20131459. https:\/\/doi.org\/10.1046\/j.1365-2168.1998.00940.x","journal-title":"Br J Surg"}],"container-title":["Virchows Archiv"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-026-04400-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00428-026-04400-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-026-04400-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T08:53:11Z","timestamp":1771404791000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00428-026-04400-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,21]]},"references-count":78,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["4400"],"URL":"https:\/\/doi.org\/10.1007\/s00428-026-04400-w","relation":{},"ISSN":["0945-6317","1432-2307"],"issn-type":[{"value":"0945-6317","type":"print"},{"value":"1432-2307","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,21]]},"assertion":[{"value":"15 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 December 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 January 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 January 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All authors declare no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interests"}}]}}