{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T16:09:14Z","timestamp":1783094954933,"version":"3.54.6"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T00:00:00Z","timestamp":1626912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Knowledge of the high microsatellite-instability (MSI-H)\/mismatch repair deficiency (MMRd) status is of increasing interest for personalized neoadjuvant or adjuvant therapy planning. Only a few studies are available on MSI-H distribution in the Northern European Caucasian patient population. In this study, we focused on a large cohort of tumors of the upper gastrointestinal tract.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>Surgical material from a total of 1,965 patients was analyzed for MSI-H\/MMRd status (including 1,267 carcinomas of the esophagus or stomach). All tumors were analyzed with an internationally recommended immunohistochemical panel consisting of four antibodies (MLH1, MSH2, PMS2, and MSH6). The results were molecularly objectified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Adenocarcinomas with MSI-H\/MMRd were detected with the following distribution: esophagus (1.4%), stomach (8.3%), small intestine (18.2%), large intestine (8.5%), intrahepatic bile ducts (1.9%), and pancreas (0%). In case of gastric tumors with MSI-H\/MMRd, neoadjuvant therapy did not influence the prognosis of patients (p = 0.94). Within all tumor entities with MSI-H\/MMRd, patients with a UICC stage 4 were also represented. In this advanced stage, 11.7% of patients with MSS tumors were diagnosed compared to 0.5% of patients with MSI-H tumors relative to the entire tumor collective.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>In this study, the proportion of MSI-H\/MMRd tumors in the stomach is smaller than would have been expected in knowledge of the data published by TCGA or AGRC. Negative prognostic effects regarding MSI-H status and neoadjuvant therapy as described by the MAGIC study group were not seen in our cohort. The extent to which the MSI-H\/MMRd status should be known for neoadjuvant therapy planning must be clarified in prospective studies in the future. At present, there is no convincing data to dispense the neoadjuvant therapy for gastric carcinoma. Due to the very convincing, positive data regarding the response rates of MSI-H tumors to treatment with PD1\/PD-L1 inhibitors, every metastatic carcinoma of the gastrointestinal tract should be tested for its MSI-H status.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2021.569475","type":"journal-article","created":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T13:04:02Z","timestamp":1627045442000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Occurrence of High Microsatellite-Instability\/Mismatch Repair Deficiency in Nearly 2,000 Human Adenocarcinomas of the Gastrointestinal Tract, Pancreas, and Bile Ducts: A Study From a Large German Comprehensive Cancer Center"],"prefix":"10.3389","volume":"11","author":[{"given":"Alexander","family":"Quaas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Rehkaemper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef","family":"Rueschoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aylin","family":"Pamuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Zander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Hillmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janna","family":"Siemanowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Wittig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhard","family":"Buettner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Plum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Popp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Gebauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane Josephine","family":"Bruns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Loeser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hakan","family":"Alakus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgid","family":"Schoemig-Markiefka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1200\/PO.17.00073","article-title":"Landscape of Microsatellite Instability Across 39 Cancer Types","volume":"1","author":"Bonneville","year":"2017","journal-title":"JCO Precis Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8484121","article-title":"Clues to the Pathogenesis of Familial Colorectal Cancer","volume":"260","author":"Aaltonen","year":"1993","journal-title":"Science"},{"key":"B3","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.jmoldx.2011.11.001","article-title":"Relevance, Pathogenesis, and Testing Algorithm for Mismatch Repair-Defective Colorectal Carcinomas: A Report of the Association for Molecular Pathology","volume":"14","author":"Funkhouser","year":"2012","journal-title":"J Mol diagnostics: JMD"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.25495","article-title":"MSI Phenotype and MMR Alterations in Familial and Sporadic Gastric Cancer","volume":"128","author":"Leite","year":"2011","journal-title":"Int J Cancer"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/s1525-1578(10)60611-3","article-title":"Detection of Microsatellite Instability by Fluorescence Multiplex Polymerase Chain Reaction","volume":"2","author":"Berg","year":"2000","journal-title":"J Mol diagnostics: JMD"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-018-2906-9","article-title":"Microsatellite Instability in Gastric Cancer: Molecular Bases, Clinical Perspectives, and New Treatment Approaches","volume":"75","author":"Ratti","year":"2018","journal-title":"Cell Mol Life sciences: CMLS"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199805213382101","article-title":"Incidence of Hereditary Nonpolyposis Colorectal Cancer and the Feasibility of Molecular Screening for the Disease","volume":"338","author":"Aaltonen","year":"1998","journal-title":"New Engl J Med"},{"key":"B8","article-title":"Diagnostic Microsatellite Instability: Definition and Correlation With Mismatch Repair Protein Expression","volume":"57","author":"Dietmaier","year":"1997","journal-title":"Cancer Res"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6602534","article-title":"Microsatellite Instability in Colorectal Cancer is Associated With Local Lymphocyte Infiltration and Low Frequency of Distant Metastases","volume":"92","author":"Buckowitz","year":"2005","journal-title":"Br J Cancer"},{"key":"B10","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1056\/NEJM200001133420201","article-title":"Tumor Microsatellite Instability and Clinical Outcome in Young Patients With Colorectal Cancer","volume":"342","author":"Gryfe","year":"2000","journal-title":"New Engl J Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1500596","article-title":"PD-1 Blockade in Tumors With Mismatch-Repair Deficiency","volume":"372","author":"Le","year":"2015","journal-title":"New Engl J Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan6733","article-title":"Mismatch Repair Deficiency Predicts Response of Solid Tumors to PD-1 Blockade","volume":"357","author":"Le","year":"2017","journal-title":"Sci (New York NY)"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1385\/1-59259-923-0:257","article-title":"Tissue Microarrays","volume":"114","author":"Simon","year":"2005","journal-title":"Methods Mol Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.7845","article-title":"Oncogene and Therapeutic Target Analyses in Atypical Fibroxanthomas and Pleomorphic Dermal Sarcomas","volume":"7","author":"Helbig","year":"2016","journal-title":"Oncotarget"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.cd-19-0487","article-title":"Genomics and Targeted Therapies in Gastroesophageal Adenocarcinoma","volume":"9","author":"Nagaraja","year":"2019","journal-title":"Cancer Discov"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1200\/jco.19.02105","article-title":"Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability\/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study","volume":"38","author":"Marabelle","year":"2019","journal-title":"J Clin Oncol: Off J Am Soc Clin Oncol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1186\/s12885-015-1093-4","article-title":"Systematic Review of the Predictive Effect of MSI Status in Colorectal Cancer Patients Undergoing 5FU-Based Chemotherapy","volume":"15","author":"Webber","year":"2015","journal-title":"BMC Cancer"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s00292-019-0610-7","article-title":"[Microsatellite Instability: Review of Methods and Applications]","volume":"40","author":"Dietmaier","year":"2019","journal-title":"Der Pathologe"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2016.6762","article-title":"Mismatch Repair Deficiency, Microsatellite Instability, and Survival: An Exploratory Analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) Trial","volume":"3","author":"Smyth","year":"2017","journal-title":"JAMA Oncol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32030","article-title":"Prognostic Significance of Microsatellite-Instability in Gastric and Gastroesophageal Junction Cancer Patients Undergoing Neoadjuvant Chemotherapy","volume":"144","author":"Haag","year":"2019","journal-title":"Int J Cancer"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/s10120-018-00918-4","article-title":"Predictive Value of MLH1 and PD-L1 Expression for Prognosis and Response to Preoperative Chemotherapy in Gastric Cancer","volume":"22","author":"Hashimoto","year":"2019","journal-title":"Gastric Cancer: Off J Int Gastric Cancer Assoc Japanese Gastric Cancer Assoc"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.21313","article-title":"Novel Strategy for Optimal Sequential Application of Clinical Criteria, Immunohistochemistry and Microsatellite Analysis in the Diagnosis of Hereditary Nonpolyposis Colorectal Cancer","volume":"118","author":"Engel","year":"2006","journal-title":"Int J Cancer"},{"key":"B23","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1093\/annonc\/mdw542","article-title":"Practical Guidance for Mismatch Repair-Deficiency Testing in Endometrial Cancer","volume":"28","author":"Stelloo","year":"2017","journal-title":"Ann Oncol: Off J Eur Soc Med Oncol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2002.37070","article-title":"Evaluation of Tumor Microsatellite Instability Using Five Quasimonomorphic Mononucleotide Repeats and Pentaplex PCR","volume":"123","author":"Suraweera","year":"2002","journal-title":"Gastroenterology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"13","DOI":"10.3390\/ijms20010013","article-title":"From Tumor Immunology to Immunotherapy in Gastric and Esophageal Cancer","volume":"20","author":"Vrana","year":"2018","journal-title":"Int J Mol Sci"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2018.02.014","article-title":"Epstein-Barr Virus and Mismatch Repair Deficiency Status Differ Between Oesophageal and Gastric Cancer: A Large Multi-Centre Study","volume":"94","author":"Hewitt","year":"2018","journal-title":"Eur J Cancer"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/nature20805","article-title":"Integrated Genomic Characterization of Oesophageal Carcinoma","volume":"541","author":"Kim","year":"2017","journal-title":"Nature"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1997.226","article-title":"Infrequent Microsatellite Instability in Oesophageal Cancers","volume":"75","author":"Muzeau","year":"1997","journal-title":"Br J Cancer"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3233\/cbm-2010-0135","article-title":"Microsatellite Instability Analysis and Its Correlation With hMLH1 Repair Gene Hypermethylation Status in Esophageal Pathologies Including Cancers","volume":"7","author":"Vasavi","year":"2010","journal-title":"Cancer Biomarkers: section A Dis Markers"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2004.03.011","article-title":"Microsatellite Instability in Esophageal Adenocarcinoma","volume":"212","author":"Evans","year":"2004","journal-title":"Cancer Lett"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.cancergencyto.2004.08.003","article-title":"Defective Mismatch-Repair as a Minor Tumorigenic Pathway in Barrett Esophagus-Associated Adenocarcinoma","volume":"157","author":"Falkenback","year":"2005","journal-title":"Cancer Genet Cytogenetics"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/eci.12163","article-title":"Distinct Genetic Aberrations in Oesophageal Adeno and Squamous Carcinoma","volume":"43","author":"Pandilla","year":"2013","journal-title":"Eur J Clin Invest"},{"key":"B33","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1097\/00019606-199409000-00032","article-title":"Microsatellite Instability in Adenocarcinomas of the Upper Gastrointestinal Tract. Relation to Clinicopathological Data and Family History","volume":"147","author":"Keller","year":"1995","journal-title":"Am J Pathol"},{"key":"B34","article-title":"Ubiquitous Somatic Alterations at Microsatellite Alleles Occur Infrequently in Barrett\u2019s-Associated Esophageal Adenocarcinoma","volume":"56","author":"Gleeson","year":"1996","journal-title":"Cancer Res"},{"key":"B35","article-title":"Microsatellite Instability Occurs Frequently and in Both Diploid and Aneuploid Cell Populations of Barrett\u2019s-Associated Esophageal Adenocarcinomas","volume":"54","author":"Meltzer","year":"1994","journal-title":"Cancer Res"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/nature13480","article-title":"Comprehensive molecular characterization of gastric adenocarcinoma","volume":"513","author":"Bass","year":"2014","journal-title":"Nature"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejso.2018.02.208","article-title":"Synchronous Metastatic Gastric Cancer-Molecular Background and Clinical Implications With Special Attention to Mismatch Repair Deficiency","volume":"44","author":"Polom","year":"2018","journal-title":"Eur J Surg Oncol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1002\/cjp2.137","article-title":"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","volume":"5","author":"Kohlruss","year":"2019","journal-title":"J Pathol Clin Res"},{"key":"B39","doi-asserted-by":"publisher","first-page":"107","DOI":"10.3390\/ijms18010107","article-title":"Clinical Significance and Prognostic Relevance of Microsatellite Instability in Sporadic Colorectal Cancer Patients","volume":"18","author":"Copija","year":"2017","journal-title":"Int J Mol Sci"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2009.237","article-title":"Microsatellite Instability in Colorectal Cancer-the Stable Evidence","volume":"7","author":"Vilar","year":"2010","journal-title":"Nat Rev Clin Oncol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007200","article-title":"Exome-Wide Somatic Mutation Characterization of Small Bowel Adenocarcinoma","volume":"14","author":"Hanninen","year":"2018","journal-title":"PloS Genet"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2017.1051","article-title":"Genomic Profiling of Small-Bowel Adenocarcinoma","volume":"3","author":"Schrock","year":"2017","journal-title":"JAMA Oncol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.569475\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T13:04:06Z","timestamp":1627045446000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.569475\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,22]]},"references-count":42,"alternative-id":["10.3389\/fonc.2021.569475"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2021.569475","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,22]]},"article-number":"569475"}}