{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T02:38:30Z","timestamp":1792723110711,"version":"4.5.0"},"reference-count":111,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,10,16]],"date-time":"2020-10-16T00:00:00Z","timestamp":1602806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The mismatch repair (MMR) system has a major role in the detection and correction of DNA replication errors, resulting from DNA polymerase slippage or nucleotides misincorporation. Specific inherited\/acquired alterations or epigenetic inactivation of MMR genes are associated with microsatellite instability (MSI): the loss of crucial function in repairing DNA alterations can promote carcinogenesis by favoring the accumulation of thousands of mutations in a broad spectrum of different anatomic sites such as colon, stomach, prostate, esophagus, endometrium, lung and head and neck. Recent extensive data suggest that tumor mutational burden strongly correlates with a clinical response to immunotherapy using checkpoint inhibitors and this response is influenced by MMR deficiency in a wide range of human solid cancers. In this context, few data about this crucial point are available for head and neck cancer (HNC). In this review, we discuss the role of MMR alterations and the resulting MSI in HNC pathogenesis. Furthermore, by summarizing the clinical available data on how they influence the progression of precancerous lesions and the risk of recurrence or second primary tumors, we want to define the current role of MSI in the management of HNC. Finally, we analyze the complex interaction between cancer cells and the immune system addressing the data now available about a potential correlation between microsatellite instability and immunotherapy response in HNC.<\/jats:p>","DOI":"10.3390\/cancers12103006","type":"journal-article","created":{"date-parts":[[2020,10,17]],"date-time":"2020-10-17T05:45:51Z","timestamp":1602913551000},"page":"3006","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["The Mismatch Repair System (MMR) in Head and Neck Carcinogenesis and Its Role in Modulating the Response to Immunotherapy: A Critical Review"],"prefix":"10.3390","volume":"12","author":[{"given":"Maria","family":"Cilona","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology, Careggi University Hospital, Largo Brambilla, 3-50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1879-5580","authenticated-orcid":false,"given":"Luca Giovanni","family":"Locatello","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Careggi University Hospital, Largo Brambilla, 3-50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Novelli","sequence":"additional","affiliation":[{"name":"Department of Pathology, Careggi University Hospital, Largo Brambilla, 3-50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3426-7179","authenticated-orcid":false,"given":"Oreste","family":"Gallo","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Careggi University Hospital, Largo Brambilla, 3-50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1056\/NEJMra1715715","article-title":"Head and Neck Cancer","volume":"382","author":"Chow","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"104460","DOI":"10.1016\/j.oraloncology.2019.104460","article-title":"Immunotherapy for head and neck cancer: Recent advances and future directions","volume":"99","author":"Cramer","year":"2019","journal-title":"Oral Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1016\/S0140-6736(19)32591-7","article-title":"Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study","volume":"394","author":"Burtness","year":"2019","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"409","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":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/S0168-9525(02)02631-8","article-title":"Microsatellite evolution: A battle between replication slippage and point mutation","volume":"18","author":"Ellegren","year":"2002","journal-title":"Trends Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"272","DOI":"10.3389\/fonc.2013.00272","article-title":"Toward a Molecular Classification of Colorectal Cancer: The Role of Microsatellite Instability Status","volume":"3","author":"Heinimann","year":"2013","journal-title":"Front. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.dnarep.2015.11.012","article-title":"The conserved molecular machinery in DNA mismatch repair enzyme structures","volume":"38","author":"Groothuizen","year":"2016","journal-title":"DNA Repair (Amst.)"},{"key":"ref_8","first-page":"241","article-title":"Mismatch repair system proteins in oral benign and malignant lesions","volume":"46","author":"Martins","year":"2016","journal-title":"J. Oral Pathol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.dnarep.2019.03.009","article-title":"The mismatch repair-dependent DNA damage response: Mechanisms and implications","volume":"78","author":"Gupta","year":"2019","journal-title":"DNA Repair (Amst.)"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.dnarep.2014.03.007","article-title":"Single molecule studies of DNA mismatch repair","volume":"20","author":"Erie","year":"2014","journal-title":"DNA Repair (Amst.)"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.mrrev.2017.07.001","article-title":"DNA mismatch repair and its many roles in eukaryotic cells","volume":"773","author":"Liu","year":"2017","journal-title":"Mutat. Res."},{"key":"ref_12","first-page":"3230","article-title":"A mutator phenotype in cancer","volume":"61","author":"Loeb","year":"2001","journal-title":"Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"18238","DOI":"10.1073\/pnas.0607057103","article-title":"Human cancers express a mutator phenotype","volume":"103","author":"Bielas","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3823","DOI":"10.4161\/15384101.2014.980633","article-title":"What is wrong with Fanconi anemia cells?","volume":"13","author":"Cantor","year":"2014","journal-title":"Cell Cycle"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"104816","DOI":"10.1016\/j.oraloncology.2020.104816","article-title":"Management of Fanconi Anemia patients with head and neck carcinoma: Diagnosis and treatment adaptation","volume":"108","author":"Beddok","year":"2020","journal-title":"Oral Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Milletti, G., Strocchio, L., Pagliara, D., Girardi, K., Carta, R., Mastronuzzi, A., Locatelli, F., and Nazio, F. (2020). Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition. Cancers, 12.","DOI":"10.3390\/cancers12092684"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Datta, A., and Brosh, R.M. (2019). Holding All the Cards\u2014How Fanconi Anemia Proteins Deal with Replication Stress and Preserve Genomic Stability. Genes, 10.","DOI":"10.3390\/genes10020170"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.15252\/embj.201387530","article-title":"Crosstalk between BRCA-F anconi anemia and mismatch repair pathways prevents MSH 2-dependent aberrant DNA damage responses","volume":"33","author":"Peng","year":"2014","journal-title":"EMBO J."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Evrard, C., Tachon, G., Randrian, V., Karayan-Tapon, L., Tougeron, D., and Tapon, K. (2019). Microsatellite Instability: Diagnosis, Heterogeneity, Discordance, and Clinical Impact in Colorectal Cancer. Cancers, 11.","DOI":"10.3390\/cancers11101567"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1200\/JCO.2005.01.086","article-title":"Systematic Review of Microsatellite Instability and Colorectal Cancer Prognosis","volume":"23","author":"Popat","year":"2005","journal-title":"J. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.ctrv.2016.10.005","article-title":"The evolving role of microsatellite instability in colorectal cancer: A review","volume":"51","author":"Gelsomino","year":"2016","journal-title":"Cancer Treat. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1158\/1055-9965.EPI-08-0878","article-title":"The association of tumor microsatellite instability phenotype with family history of colorectal cancer","volume":"18","author":"Bapat","year":"2009","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1056\/NEJMcp1714533","article-title":"Lynch Syndrome\u2013Associated Colorectal Cancer","volume":"379","author":"Sinicrope","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"iv283","DOI":"10.1093\/annonc\/mdh940","article-title":"Importance of microsatellite instability (MSI) in colorectal cancer: MSI as a diagnostic tool","volume":"15","author":"Kurzawski","year":"2004","journal-title":"Ann. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3219","DOI":"10.1200\/JCO.2009.27.1825","article-title":"Defective Mismatch Repair As a Predictive Marker for Lack of Efficacy of Fluorouracil-Based Adjuvant Therapy in Colon Cancer","volume":"28","author":"Sargent","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1200\/JCO.2008.18.2071","article-title":"Microsatellite Instability Predicts Improved Response to Adjuvant Therapy With Irinotecan, Fluorouracil, and Leucovorin in Stage III Colon Cancer: Cancer and Leukemia Group B Protocol 89803","volume":"27","author":"Bertagnolli","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_27","first-page":"1773","article-title":"Relationship between microsatellite instability, response and survival in palliative patients with colorectal cancer undergoing first-line chemotherapy","volume":"23","author":"Brueckl","year":"2003","journal-title":"Anticancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1002\/ijc.10643","article-title":"High-frequency microsatellite instability predicts better chemosensitivity to high-dose 5-fluorouracil plus leucovorin chemotherapy for stage IV sporadic colorectal cancer after palliative bowel resection","volume":"101","author":"Liang","year":"2002","journal-title":"Int. J. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4132\/KoreanJPathol.2013.47.1.1","article-title":"Radiotherapy Response in Microsatellite Instability Related Rectal Cancer","volume":"47","author":"Shin","year":"2013","journal-title":"Korean J. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.pharmthera.2018.04.004","article-title":"DNA mismatch repair in cancer","volume":"189","author":"Baretti","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1007\/s00204-015-1474-0","article-title":"Microsatellite instability: An update","volume":"89","author":"Yamamoto","year":"2015","journal-title":"Arch. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"293","DOI":"10.2353\/jmoldx.2008.080031","article-title":"Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part I. The utility of immunohistochemistry","volume":"10","author":"Shia","year":"2008","journal-title":"J. Mol. Diagn."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1634\/theoncologist.2016-0046","article-title":"Mismatch Repair Deficiency and Response to Immune Checkpoint Blockade","volume":"21","author":"Lee","year":"2016","journal-title":"Oncologist"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/S1525-1578(10)60526-0","article-title":"Challenges and Pitfalls in HNPCC Screening by Microsatellite Analysis and Immunohistochemistry","volume":"6","author":"Edmonston","year":"2004","journal-title":"J. Mol. Diagn."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1002\/cjp2.120","article-title":"Heterogenous loss of mismatch repair (MMR) protein expression: A challenge for immunohistochemical interpretation and microsatellite instability (MSI) evaluation","volume":"5","author":"McCarthy","year":"2018","journal-title":"J. Pathol. Clin. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1002\/cbf.3428","article-title":"Involvement of repair genes in oral cancer: A systematic review","volume":"37","author":"Fonseca","year":"2019","journal-title":"Cell Biochem. Funct."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1038\/sj.ejhg.5201845","article-title":"The clinical relevance of microsatellite alterations in head and neck squamous cell carcinoma: A critical review","volume":"15","author":"Spaepen","year":"2007","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/ijc.1337","article-title":"High frequency of microsatellite instability in young patients with head-and-neck squamous-cell carcinoma: Lack of involvement of the mismatch repair genes hMLH1 AND hMSH2","volume":"93","author":"Wang","year":"2001","journal-title":"Int. J. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1054\/ijom.2001.0161","article-title":"Genetic analysis of DNA microsatellite loci in salivary gland tumours: Comparison with immunohistochemical detection of hMSH2 and p53 proteins","volume":"30","author":"Ohki","year":"2001","journal-title":"Int. J. Oral Maxillofac. Surg."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1002\/ijc.10748","article-title":"Progression of microsatellite instability from premalignant lesions to tumors of the head and neck","volume":"102","author":"Ha","year":"2002","journal-title":"Int. J. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1034\/j.1600-0714.2002.310407.x","article-title":"Expression of hMSH2 and hMLH1 proteins of the human DNA mismatch repair system in salivary gland tumors","volume":"31","author":"Castrilli","year":"2002","journal-title":"J. Oral Pathol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"146","DOI":"10.7150\/ijms.1.146","article-title":"Expression of hMSH2 protein of the human DNA mismatch repair system in oral lichen planus","volume":"1","author":"Pimenta","year":"2004","journal-title":"Int. J. Med. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1002\/hed.20390","article-title":"Microsatellite instability as an indicator of malignant progression in laryngeal premalignancy","volume":"28","author":"Sardi","year":"2006","journal-title":"Head Neck"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1093\/annonc\/mdl048","article-title":"Microsatellite instability and methylation of the DNA mismatch repair genes in head and neck cancer","volume":"17","author":"Demokan","year":"2006","journal-title":"Ann. Oncol."},{"key":"ref_45","first-page":"251","article-title":"HMSH2 gene alterations associated with recurrence of oral squamous cell carcinoma","volume":"25","author":"Sanguansin","year":"2006","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1002\/cncr.22430","article-title":"Inactivation of human mutL homolog 1 and mutS homolog 2 genes in head and neck squamous cell carcinoma tumors and leukoplakia samples by promoter hypermethylation and its relation with microsatellite instability phenotype","volume":"109","author":"Sengupta","year":"2007","journal-title":"Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1111\/j.1601-0825.2008.01510.x","article-title":"Promoter hypermethylation of mismatch repair genes, hMLH1 and hMSH2in oral squamous cell carcinoma","volume":"15","author":"Czerninski","year":"2009","journal-title":"Oral Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.tripleo.2009.02.033","article-title":"Expression of hMLH1 and hMSH2 proteins in pleomorphic adenoma of minor salivary glands: Relationship with clinical and histologic findings","volume":"108","year":"2009","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endodontol."},{"key":"ref_49","first-page":"485","article-title":"The prevalence of microsatellite instability in head and neck squamous cell carcinoma","volume":"135","author":"Spaepen","year":"2008","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3541","DOI":"10.1007\/s11033-010-0001-x","article-title":"Assessment of microsatellite instability in head and neck cancer using consensus markers","volume":"37","author":"Yalniz","year":"2010","journal-title":"Mol. Biol. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.oraloncology.2011.03.005","article-title":"Microsatellite instability and loss of heterozygosity in oral squamous cell carcinoma in Malaysian population","volume":"47","author":"Ashazila","year":"2011","journal-title":"Oral Oncol."},{"key":"ref_52","first-page":"528","article-title":"Head and neck squamous cell carcinoma: Mismatch repair immunohistochemistry and promoter hypermethylation of hMLH1 gene","volume":"32","author":"Tawfik","year":"2011","journal-title":"Am. J. Otolaryngol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1111\/j.1600-0714.2010.00963.x","article-title":"hMLH1 immunoexpression is related to the degree of epithelial dysplasia in oral leukoplakia","volume":"40","author":"Caldeira","year":"2010","journal-title":"J. Oral Pathol. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1111\/j.1600-0714.2010.01000.x","article-title":"Oral leukoplakias with different degrees of dysplasia: Comparative study of hMLH1, p53, and AgNOR","volume":"40","author":"Caldeira","year":"2011","journal-title":"J. Oral Pathol. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1111\/j.1365-2559.2011.03756.x","article-title":"Immunohistochemical analysis of p53, APE1, hMSH2 and ERCC1 proteins in actinic cheilitis and lip squamous cell carcinoma","volume":"58","author":"Souza","year":"2011","journal-title":"Histopathology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.oraloncology.2010.10.002","article-title":"hMLH1 promoter methylation is an early event in oral cancer","volume":"47","author":"Irigoyen","year":"2011","journal-title":"Oral Oncol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1111\/j.1600-0714.2010.00945.x","article-title":"Expression of DNA repair proteins, MSH2, MLH1 and MGMT in mobile tongue squamous cell carcinoma: Associations with clinicopathological parameters and patients\u2019 survival","volume":"40","author":"Theocharis","year":"2010","journal-title":"J. Oral Pathol. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.oraloncology.2011.08.024","article-title":"Immunoexpression of p53 and hMSH2 in oral squamous cell carcinoma and oral dysplastic lesions in Yemen: Relationship to oral risk habits and prognostic factors","volume":"48","author":"Helal","year":"2012","journal-title":"Oral Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1111\/his.12197","article-title":"Immunohistochemical analysis of mismatch proteins in carcinogenesis of the lower lip","volume":"63","author":"Sarmento","year":"2013","journal-title":"Histopathology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.gene.2013.05.014","article-title":"Single nucleotide polymorphism in hMLH1 promoter and risk of tobacco-related oral carcinoma in high-risk Asian Indians","volume":"526","author":"Jha","year":"2013","journal-title":"Gene"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Mondal, P., Datta, S., Maiti, G.P., Baral, A., Jha, G.N., Panda, C.K., Chowdhury, S., Ghosh, S., Roy, B., and Roychoudhury, S. (2013). Comprehensive SNP Scan of DNA Repair and DNA Damage Response Genes Reveal Multiple Susceptibility Loci Conferring Risk to Tobacco Associated Leukoplakia and Oral Cancer. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0056952"},{"key":"ref_62","first-page":"357","article-title":"Relationship between the epithelial expression of hMLH1, MDM2, and p63 and lower lip carcinogenesis","volume":"43","author":"Queiroz","year":"2013","journal-title":"J. Oral Pathol. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1002\/ijc.29435","article-title":"Association between genetic polymorphisms in DNA mismatch repair-related genes with risk and prognosis of head and neck squamous cell carcinoma","volume":"137","author":"Nogueira","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1136\/jclinpath-2014-202411","article-title":"hMSH6: A potential diagnostic marker for oral carcinoma in situ","volume":"68","author":"Jessri","year":"2014","journal-title":"J. Clin. Pathol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.oooo.2014.06.017","article-title":"MutS\u03b1 and MutL\u03b1 immunoexpression analysis in diagnostic grading of oral epithelial dysplasia and squamous cell carcinoma","volume":"119","author":"Jessri","year":"2015","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s00403-016-1625-z","article-title":"Correlation between cell cycle proteins and hMSH2 in actinic cheilitis and lip cancer","volume":"308","author":"Lopes","year":"2016","journal-title":"Arch. Dermatol. Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1016\/j.pathol.2019.08.005","article-title":"Tumour mismatch repair protein loss is associated with advanced stage in oral cavity squamous cell carcinoma","volume":"51","author":"Vasan","year":"2019","journal-title":"Pathology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1056\/NEJMra072067","article-title":"Epigenetics in Cancer","volume":"358","author":"Esteller","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1007\/s10147-014-0780-5","article-title":"A methylation-specific dot blot assay for improving specificity and sensitivity of methylation-specific PCR on DNA methylation analysis","volume":"20","author":"Lan","year":"2015","journal-title":"Int. J. Clin. Oncol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1093\/carcin\/bgr089","article-title":"MLH1-93G > A is a risk factor for MSI colorectal cancer","volume":"32","author":"Whiffin","year":"2011","journal-title":"Carcinogenesis"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/5584_2014_83","article-title":"Mismatch Repair Gene Polymorphisms and Association with Lung Cancer Development","volume":"833","author":"Matakova","year":"2014","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"44","DOI":"10.31768\/2312-8852.2015.37(1):44-47","article-title":"Polymorphism of DNA mismatch repair genes in endometrial cancer","volume":"37","author":"Sobczuk","year":"2015","journal-title":"Exp. Oncol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"222","DOI":"10.4103\/0019-5154.156315","article-title":"Oral lichen planus: An update on etiology, pathogenesis, clinical presentation, diagnosis and management","volume":"60","author":"Gupta","year":"2015","journal-title":"Indian J. Dermatol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1001\/jamadermatol.2019.3797","article-title":"Global Prevalence and Incidence Estimates of Oral Lichen Planus: A Systematic Review and Meta-analysis","volume":"156","author":"Li","year":"2020","journal-title":"JAMA Dermatol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1002\/1098-2264(2000)9999:9999<::AID-GCC1031>3.0.CO;2-X","article-title":"Prediction of recurrence by microsatellite analysis in head and neck cancer","volume":"29","author":"Sardi","year":"2000","journal-title":"Genes Chromosom. Cancer"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1034\/j.1601-0825.2002.02870.x","article-title":"Salivary gland tumours","volume":"8","author":"Speight","year":"2002","journal-title":"Oral Dis."},{"key":"ref_77","unstructured":"McGurk, M., and Renehan, A. (2001). What is the evidence for the progression from benign to malignant pleomorphic adenoma?. Controversies in the Management of Salivary Gland Disease, Oxford University Press."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"4022","DOI":"10.1158\/1078-0432.CCR-04-0199","article-title":"Tetranucleotide Microsatellite Instability in Surgical Margins for Prediction of Local Recurrence of Head and Neck Squamous Cell Carcinoma","volume":"10 Pt 1","author":"Temam","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s00405-016-4215-y","article-title":"Impact of microsatellite alteration in surgical margins on local recurrence in oral cavity cancer patients","volume":"274","author":"Lin","year":"2016","journal-title":"Eur. Arch. Oto-Rhino-Laryngol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e142","DOI":"10.1002\/bjs.10693","article-title":"Genetic analysis of surgical margins in oral cavity cancer","volume":"105","author":"Liu","year":"2018","journal-title":"Br. J. Surg."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1002\/1097-0142(195309)6:5<963::AID-CNCR2820060515>3.0.CO;2-Q","article-title":"Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin","volume":"6","author":"Slaughter","year":"1953","journal-title":"Cancer"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrc2982","article-title":"The molecular biology of head and neck cancer","volume":"11","author":"Leemans","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1097\/00001622-200205000-00010","article-title":"Genetic susceptibility\u2013molecular epidemiology of head and neck cancer","volume":"14","author":"Sturgis","year":"2002","journal-title":"Curr. Opin. Oncol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.3389\/fonc.2019.01275","article-title":"Susceptibility of Multiple Primary Cancers in Patients With Head and Neck Cancer: Nature or Nurture?","volume":"9","author":"Zhang","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1038\/bjc.1998.644","article-title":"Microsatellite instability in squamous cell carcinomas of the head and neck related to field cancerization phenomena","volume":"78","author":"Piccinin","year":"1998","journal-title":"Br. J. Cancer"},{"key":"ref_86","first-page":"2771","article-title":"Microsatellite analyses of recurrence or second primary tumor in head and neck cancer","volume":"25","author":"Ronchetti","year":"2005","journal-title":"Anticancer Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1177\/0194599813484273","article-title":"Risk Factors for Multiple Malignancies in the Head and Neck","volume":"149","author":"Deganello","year":"2013","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1080\/14712598.2019.1556637","article-title":"The value of immunotherapy in head and neck cancer","volume":"19","author":"Manca","year":"2018","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"93","DOI":"10.3892\/etm_00000017","article-title":"Human MLH1 status can potentially predict cisplatin sensitivity but not microsatellite instability in head and neck squamous cell carcinoma cells","volume":"1","author":"Adachi","year":"2010","journal-title":"Exp. Ther. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1002\/(SICI)1097-0215(19990820)84:4<410::AID-IJC14>3.0.CO;2-J","article-title":"Microsatellite analysis and response to chemotherapy in head-and-neck squamous-cell carcinoma","volume":"84","author":"Blons","year":"1999","journal-title":"Int. J. Cancer"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3391","DOI":"10.1158\/0008-5472.CAN-04-0513","article-title":"Dependence of the Cytotoxicity of DNA-Damaging Agents on the Mismatch Repair Status of Human Cells","volume":"64","author":"Papouli","year":"2004","journal-title":"Cancer Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1093\/carcin\/22.12.1931","article-title":"Mechanisms of tolerance to DNA damaging therapeutic drugs","volume":"22","author":"Karran","year":"2001","journal-title":"Carcinogenesis"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/s41591-019-0434-2","article-title":"Immunogenic neoantigens derived from gene fusions stimulate T cell responses","volume":"25","author":"Yang","year":"2019","journal-title":"Nat. Med."},{"key":"ref_94","first-page":"479","article-title":"Neoantigen-directed immune escape in lung cancer evolution","volume":"567","author":"Rosenthal","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/j.csbj.2019.03.006","article-title":"Application of PD-1 Blockade in Cancer Immunotherapy","volume":"17","author":"Wu","year":"2019","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"12293","DOI":"10.1073\/pnas.192461099","article-title":"Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade","volume":"99","author":"Iwai","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1001\/jamaoncol.2020.0504","article-title":"Efficacy of Immunotherapy in Microsatellite-Stable or Mismatch Repair Proficient Colorectal Cancer\u2014Fact or Fiction?","volume":"6","author":"Corcoran","year":"2020","journal-title":"JAMA Oncol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/s41588-018-0312-8","article-title":"Tumor mutational load predicts survival after immunotherapy across multiple cancer types","volume":"51","author":"Samstein","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"3415","DOI":"10.1111\/cas.14197","article-title":"Regulation of programmed death-ligand 1 expression in response to DNA damage in cancer cells: Implications for precision medicine","volume":"110","author":"Sato","year":"2019","journal-title":"Cancer Sci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1093\/annonc\/mdz116","article-title":"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","volume":"30","author":"Luchini","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1056\/NEJMoa1500596","article-title":"PD-1 Blockade in Tumors with Mismatch-Repair Deficiency","volume":"372","author":"Le","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.bulcan.2018.08.007","article-title":"Why is immunotherapy effective (or not) in patients with MSI\/MMRD tumors?","volume":"106","author":"Coutzac","year":"2019","journal-title":"Bull. Cancer"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1126\/science.aau0447","article-title":"Genetic diversity of tumors with mismatch repair deficiency influences anti\u2013PD-1 immunotherapy response","volume":"364","author":"Mandal","year":"2019","journal-title":"Science"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"295","DOI":"10.2147\/TCRM.S125059","article-title":"New developments in the management of head and neck cancer\u2014impact of pembrolizumab","volume":"14","author":"Saleh","year":"2018","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.oraloncology.2018.04.008","article-title":"Nivolumab vs investigator\u2019s choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression","volume":"81","author":"Ferris","year":"2018","journal-title":"Oral Oncol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/S1470-2045(16)30066-3","article-title":"Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): An open-label, multicentre, phase 1b trial","volume":"17","author":"Seiwert","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"3838","DOI":"10.1200\/JCO.2016.68.1478","article-title":"Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and\/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort","volume":"34","author":"Chow","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_108","unstructured":"(2020, September 27). PD-L1 IHC 22C3 pharmDx for Autostainer Link 48. Available online: https:\/\/www.agilent.com\/en\/product\/pharmdx\/pd-l1-ihc-22c3-pharmdx\/pd-l1-ihc-22c3-pharmdx-for-autostainer-link-48-94448."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1002\/hed.26036","article-title":"Impact of PD-L1 expression and human papillomavirus status in anti-PD1\/PDL1 immunotherapy for head and neck squamous cell carcinoma\u2014Systematic review and meta-analysis","volume":"42","author":"Patel","year":"2020","journal-title":"Head Neck"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1200\/JCO.2016.70.1524","article-title":"Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study","volume":"35","author":"Bauml","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.oraloncology.2018.04.001","article-title":"Microsatellite instability associated with durable complete response to PD-L1 inhibitor in head and neck squamous cell carcinoma","volume":"80","author":"Tardy","year":"2018","journal-title":"Oral Oncol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/10\/3006\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:22:35Z","timestamp":1760178155000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/10\/3006"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,16]]},"references-count":111,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["cancers12103006"],"URL":"https:\/\/doi.org\/10.3390\/cancers12103006","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,16]]}}}