Kazan medical journalKazan medical journalКазанский медицинский журнал0368-48142587-9359Eco-Vector56795010.17816/KMJ567950ReviewsОбзорыReview ArticleMicrosatellite instability in precancerous changes in the gastric mucosaМикросателлитная нестабильность в предраковых изменениях слизистой оболочки желудкаhttps://orcid.org/0000-0001-8006-3260ParyginaMaria N.ПарыгинаМария Николаевна
Russian Federation

M.D., Cand. Sci. (Med.), Assistant, Depart. of Pathological Anatomy

канд. мед. наук, асс., каф. патологической анатомии

mariyakern@gmail.comhttps://orcid.org/0000-0003-1834-3629RubtsovVyacheslav A.РубцовВячеслав Александрович
Russian Federation

M.D., Cand. Sci. (Med.), Assoc. Prof., Depart. of Pathological Anatom

канд. мед. наук, доц., каф. патологической анатомии

rubtsov.omgmu@mail.ruhttps://orcid.org/0009-0006-9483-869XIvanovaSofia V.ИвановаСофья Владимировна
Russian Federation

Student

Студент

sofiaVesk@yandex.ruhttps://orcid.org/0000-0003-0949-8709ShimanskayaAnna G.ШиманскаяАнна Геннадьевна
Russian Federation

M.D., Cand. Sci. (Med.), Assoc. Prof., Depart. of Pathological Anatomy

канд. мед. наук, доц., каф. патологической анатомии

shimansckaya.anna@yandex.ruhttps://orcid.org/0000-0001-8607-7831KononovAlexei V.КононовАлексей Владимирович
Russian Federation

M.D., D. Sci. (Med.), Prof., Head of Depart., Depart. of Pathological Anatomy

докт. мед. наук, проф., зав. каф., каф. патологической анатомии

ogmapath@mail.ruOmsk State Medical UniversityОмский государственный медицинский университет281220230202202410511181270910202320112023Copyright ©; 2024, Eco-VectorCopyright ©; 2024, Эко-Вектор2024Eco-VectorЭко-Векторhttp://creativecommons.org/licenses/by-nc-sa/4.0https://kazanmedjournal.ru/kazanmedj/article/view/567950

Microsatellite instability is a widely known and sought after tumor marker. Among other things, its prevalence and role in the development of gastric adenocarcinoma are being studied. However, the profile of microsatellite instability during precancerous changes in the gastric mucosa (atrophy, intestinal metaplasia, epithelial dysplasia) remains insufficiently studied. The purpose of this literature review is to assess the possibility of using microsatellite instability status as a diagnostic and predictive marker of precancerous changes and lesions of the gastric mucosa. A systematic review of publications in the PubMed database was conducted using a search query based on the combination of the terms “microsatellite instability” (“MSI”), “stomach/gastric cancer/adenocarcinoma”, “stomach/gastric dysplasia/intraepithelial neoplasia”, “stomach/gastric precancerous lesions” for the period from 1997 to 2023. Review articles were excluded from the search results. The systematic review included 11 relevant publications. Despite the lack of a uniform methodology and diversity in the study groups, all publications demonstrated an increase in the level of microsatellite instability in the range from normal (unchanged) gastric mucosa and/or its precancerous changes to gastric cancer: among precancerous changes in the gastric mucosa, the most common subject of study was intestinal metaplasia, where levels of microsatellite instability ranged from 0 to 53.3%, while its levels in gastric cancer ranged from 32.6 to 76.7%. The results of the studies included in the review may indicate a possible predictive role of microsatellite instability in precancerous changes in the gastric mucosa in relation to the risk of developing cancer.

Микросателлитная нестабильность — широко известный и востребованный маркёр опухолей. В числе прочего исследуют её распространённость и роль в развитии аденокарциномы желудка. Однако профиль микросателлитной нестабильности при предраковых изменениях слизистой оболочки желудка (атрофии, кишечной метаплазии, дисплазии эпителия) остаётся недостаточно изученным. Цель настоящего литературного обзора — оценка возможности использования статуса микросателлитной нестабильности как диагностического и предиктивного маркёра предраковых изменений и поражений слизистой оболочки желудка. Проведён систематический обзор публикаций базы данных PubMed с использованием поискового запроса, основанного на комбинации терминов «микросателлитная нестабильность» («microsatellite instability»/«MSI»), «рак желудка»/«аденокарцинома желудка» («stomach/gastric cancer/adenocarcinoma»), «дисплазия/интраэпителиальная неоплазия желудка» («stomach/gastric dysplasia/intraepithelial neoplasia»), «предраковые изменения желудка» («stomach/gastric precancerous lesions») за период с 1997 по 2023 г. Из результатов поиска исключены обзорные статьи. В систематический обзор вошло 11 релевантных публикаций. Несмотря на отсутствие единой методологии и разнообразие в исследуемых группах, во всех публикациях продемонстрировано увеличение уровня микросателлитной нестабильности в ряду от нормальной (неизменённой) слизистой оболочки желудка и/или предраковых её изменений до рака желудка: среди предраковых изменений слизистой оболочки желудка наиболее частым предметом исследования была кишечная метаплазия, где уровни микросателлитной нестабильности варьировали от 0 до 53,3%, тогда как её уровни при раке желудка находились в диапазоне от 32,6 до 76,7%. Результаты работ, включённых в обзор, могут указывать на возможную предиктивную роль микросателлитной нестабильности при предраковых изменениях слизистой оболочки желудка в отношении риска развития рака.

reviewmicrosatellite instabilityatrophy of the gastric mucosaepithelial dysplasiagastric cancercancer predictionобзормикросателлитная нестабильностьатрофия слизистой оболочки желудкадисплазия эпителиярак желудкаканцерпредикцияРоссийский научный фондThe Russian Science Foundation23–25–10036Vaksman Z, Garner HR. Somatic microsatellite variability as a predictive marker for colorectal cancer and liver cancer progression. Oncotarget. 2015;6:5760–5771. DOI: 10.18632/oncotarget.3306.Liehr T. Repetitive elements in humans. Int J Mol Sci. 2021;22(4):2072. DOI: 10.3390/ijms22042072.Miller CJ, Usdin K. Mismatch repair is a double-edged sword in the battle against microsatellite instability. Expert Rev Mol Med. 2022;24:e32. DOI: 10.1017/erm.2022.16.Kurbatov V, Khan SA. Exploring microsatellite instability (MSI) in colorectal cancer at elevated microsatellite alterations at selected tetranucleotides (EMAST). Ann Surg Oncol. 2020;27(4):973–974. DOI: 10.1245/s10434-019-08051-x.Li K, Luo H, Huang L, Luo H, Zhu X. Microsatellite instability: A review of what the oncologist should know. Cancer Cell Int. 2020;20:16. DOI: 10.1186/s12935-019-1091-8.Wang Z, Moffitt AB, Andrews P, Wigler M, Levy D. Accurate measurement of microsatellite length by disrupting its tandem repeat structure. Nucleic Acids Res. 2022;50(20):e116. DOI: 10.1093/nar/gkac723.Yang G, Zheng RY, Jin ZS. Correlations between microsatellite instability and the biological behaviour of tumours. J Cancer Res Clin Oncol. 2019;145(12):2891–2899. DOI: 10.1007/s00432-019-03053-4.Chistiakov DA, Hellemans B, Volckaert FAM. Microsatellites and their genomic distribution, evolution, function and applications: A review with special reference to fish genetics. Aquaculture. 2006;255:1–29. DOI: 10.1016/j.aquaculture.2005.11.031.Srivastava S, Avvaru AK, Sowpati DT, Mishra RK. Patterns of microsatellite distribution across eukaryotic genomes. BMC Genomics. 2019;20(1):153. DOI: 10.1186/s12864-019-5516-5.Wright SE, Todd PK. Native functions of short tandem repeats. Elife. 2023;12:e84043. DOI: 10.7554/eLife.84043.Gadgil R, Barthelemy J, Lewis T, Leffak M. Replication stalling and DNA microsatellite instability. Biophys Chem. 2017;225:38–48. DOI: 10.1016/j.bpc.2016.11.007.Amaral-Silva GK, Martins MD, Pontes HA, Fregnani ER, Lopes MA, Fonseca FP, Vargas PA. Mismatch repair system proteins in oral benign and malignant lesions. J Oral Pathol Med. 2017;46(4):241–245. DOI: 10.1111/jop.12484.Salem ME, Bodor JN, Puccini A, Xiu J, Goldberg RM, Grothey A, Korn WM, Shields AF, Worrilow WM, Kim ES, Lenz HJ, Marshall JL, Hall MJ. Relationship between MLH1, PMS2, MSH2 and MSH6 gene-specific alterations and tumor mutational burden in 1057 microsatellite instability-high solid tumors. Int J Cancer. 2020;147(10):2948–2956. DOI: 10.1002/ijc.33115.Cherri S, Oneda E, Noventa S, Melocchi L, Zaniboni A. Microsatellite instability and chemosensitivity in solid tumours. Ther Adv Med Oncol. 2022;14:17588359221099347. DOI: 10.1177/17588359221099347.Randrian V, Evrard C, Tougeron D. Microsatellite instability in colorectal cancers: Carcinogenesis, neo-antigens, immuno-resistance and emerging therapies. Cancers. 2021;13(12):3063. DOI: 10.3390/cancers13123063.Luchini C, Bibeau F, Ligtenberg MJL, Singh N, Nottegar A, Bosse T, Miller R, Riaz N, Douillard JY, Andre F, Scarpa A. 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. 2019;30(8):1232–1243. DOI: 10.1093/annonc/mdz116.Abdel-Rahman WM. Genomic instability and carcinogenesis: An update. Curr Genomics. 2008;9(8):535–541. DOI: 10.2174/138920208786847926.Eso Y, Shimizu T, Takeda H, Takai A, Marusawa H. Microsatellite instability and immune checkpoint inhibitors: Toward precision medicine against gastrointestinal and hepatobiliary cancers. J Gastroenterol. 2020;55(1):15–26. DOI: 10.1007/s00535-019-01620-7.WHO classification of tumours. Digestive system tumours. 5th ed. I.A. Cree, editor. IARC; 2019. 635 p.WHO classification of tumours. Female genital tumours. 5th ed. I.A. Cree, editor. IARC; 2020. 632 p.Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–209. DOI: 10.1038/nature13480.Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, Liu J, Yue YG, Wang J, Yu K, Ye XS, Do IG, Liu S, Gong L, Fu J, Jin JG, Choi MG, Sohn TS, Lee JH, Bae JM, Kim ST, Park SH, Sohn I, Jung SH, Tan P, Chen R, Hardwick J, Kang WK, Ayers M, Hongyue D, Reinhard C, Loboda A, Kim S, Aggarwal A. Molecular analysis of gastric cancer identifies subtypes associated with distinct cli-nical outcomes. Nat Med. 2015;21:449–456. DOI: 10.1038/nm.3850.Polom K, Marano L, Marrelli D, De Luca R, Roviello G, Savelli V, Tan P, Roviello F. Meta-analysis of microsatellite instability in relation to clinicopathological characteristics and overall survival in gastric cancer. Br J Surgery. 2018;105:159–167. DOI: 10.1002/bjs.10663.Puliga E, Corso S, Pietrantonio F, Giordano S. Microsatellite instability in gastric cancer: Between lights and shadows. Cancer Treat Rev. 2021;95:102175. DOI: 10.1016/j.ctrv.2021.102175.Zubarayev M, Min E-K, Son T. Clinical and molecular prognostic markers of survival after surgery for gastric cancer: tumor-node-metastasis staging system and beyond. Transl Gastroenterol Hepatol. 2019;4:59. DOI: 10.21037/ tgh.2019.08.05.Martinez-Ciarpaglini C, Fleitas-Kanonnikoff T, Gambardella V, Llorca M, Mongort C, Mengual R, Nieto G, Navarro L, Huerta M, Rosello S, Roda D, Tarazona N, Navarro S, Ribas G, Cervantes A. Assessing molecular subtypes of gastric cancer: Microsatellite unstable and Epstein–Barr virus subtypes. Methods for detection and clinical and pathological implications. ESMO Open. 2019;4:e000470. DOI: 10.1136/esmoopen-2018-000470.Kim J-Y, Shin NR, Kim A, Lee HJ, Park WY, Kim JY, Lee CH, Huh GY, Park DY. Microsatellite instability status in gastric cancer: A reappraisal of its clinical significance and relationship with mucin phenotypes. Korean J Pathol. 2013;47:28–35. DOI: 10.4132/Korean JPathol.2013.47.1.28.Mathiak M, Warneke VS, Behrens H-M, Haag J, Böger C, Krüger S, Röcken C. Clinicopathologic characteristics of microsatellite instable gastric carcinomas revisited: Urgent need for standardization. Appl Immunohistochem Mol Morphol. 2017;25:12–24. DOI: 10.1097/PAI.0000000000000264.Leite M, Corso G, Sousa S, Milanezi F, Afonso LP, Henrique R, Soares JM, Castedo S, Carneiro F, Roviello F, Oliveira C, Seruca R. MSI phenotype and MMR alterations in familial and sporadic gastric cancer. Int J Cancer. 2011;128:1606–1613. DOI: 10.1002/ijc.25495.Pedrazzani C, Corso G, Velho S, Leite M, Pascale V, Bettarini F, Marrelli D, Seruca R, Roviello F. Evidence of tumor microsatellite instability in gastric cancer with familial aggregation. Fam Cancer. 2009;8:215–220. DOI: 10.1007/s10689-008-9231-7.Polom K, Marrelli D, Voglino C, Roviello G, De Franco L, Vindigni C, Generali D, Roviello F. Familial aggregation of gastric cancer with microsatellite instability. Acta Chir Belg. 2018;118:287–293. DOI: 10.1080/00015458.2017.1379789.Tian R, Hu J, Ma X, Liang L, Guo S. Immune-related gene signature predicts overall survival of gastric cancer patients with varying microsatellite instability status. Aging (Albany NY). 2020;13(2):2418–2435. DOI: 10.18632/aging.202271.Challine A, Karoui M, De La Fouchardière C, André T, Svrcek M, Meeus P, Dupré A, Paye F, Benoit S, Denet C, Eveno C, Lefèvre JH, Parc Y. Outcomes of surgical resection in microsatellite instable colorectal cancer after immune checkpoint inhibitor treatment. Br J Surg. 2023;110(9):1043–1045. DOI: 10.1093/bjs/znac425.Danilova NV, Chayka AV, Khomyakov VM, Oleynikova NA, Andreeva YuYu, Malkov PG. Microsatellite instability in gastric cancer is a predictor of favorable prognosis. Arkhiv patologii. 2022;84(6):5–15. (In Russ.) DOI: 10.17116/patol2022840615.Данилова Н.В., Чайка А.В., Хомяков В.М., Олейникова Н.А., Андреева Ю.Ю., Мальков П.Г. Микросателлитная нестабильность в раке желудка — предиктор благоприятного прогноза. Архив патологии. 2022; 84(6):5–15. DOI: 10.17116/patol2022840615.Correa P. Chronic gastritis: A clinico-pathological classification. Am J Gastroenterol. 1988;83(5):504–509. PMID: 3364410.Hamamoto T, Yokozaki H, Semba S, Yasui W, Yunotani S, Miyazaki K, Tahara E. Altered microsatellites in incomplete-type intestinal metaplasia adjacent to primary gastric cancers. J Clin Pathol. 1997;50(10):841–846. DOI: 10.1136/jcp.50.10.841.Fang DC, Jass JR, Wang DX, Zhou XD, Luo YH, Young J. Infrequent loss of heterozygosity of APC/MCC and DCC genes in gastric cancer showing DNA microsatellite instability. J Clin Pathol. 1999;52(7):504–508. DOI: 10.1136/jcp.52.7.504.Kobayashi K, Okamoto T, Takayama S, Akiyama M, Ohno T, Yamada H. Genetic instability in intestinal metaplasia is a frequent event leading to well-differentiated early adenocarcinoma of the stomach. Eur J Cancer. 2000;36(9):1113–1119. DOI: 10.1016/s0959-8049(00)00066-6.Leung WK, Kim JJ, Kim JG, Graham DY, Sepulveda AR. Microsatellite instability in gastric intestinal metaplasia in patients with and without gastric cancer. Am J Pathol. 2000;156(2):537–543. DOI: 10.1016/S0002-9440(10)64758-X.Garay J, Bravo JC, Correa P, Schneider BG. Infrequency of microsatellite instability in complete and incomplete gastric intestinal metaplasia. Hum Pathol. 2004;35(1):102–106. DOI: 10.1016/j.humpath.2003.08.023.Li JH, Shi XZ, Lv S, Liu M, Xu GW. Effect of Helicobacter pylori infection on p53 expression of gastric mucosa and adenocarcinoma with microsatellite instability. World J Gastroenterol. 2005;11(28):4363–4366. DOI: 10.3748/wjg.v11.i28.4363.Liu P, Zhang XY, Shao Y, Zhang DF. Microsatellite instability in gastric cancer and pre-cancerous lesions. World J Gastroenterol. 2005;11(31):4904–4907. DOI: 10.3748/wjg.v11.i31.4904.Zaky AH, Watari J, Tanabe H, Sato R, Moriichi K, Tanaka A, Maemoto A, Fujiya M, Ashida T, Kohgo Y. Clinicopathologic implications of genetic instability in intestinal-type gastric cancer and intestinal metaplasia as a precancerous lesion: Proof of field cancerization in the stomach. Am J Clin Pathol. 2008;129(4):613–621. DOI: 10.1309/DFLELPGPNV5LK6B1.Sugai T, Habano W, Jiao YF, Toyota M, Suzuki H, Tsukahara M, Koizuka H, Akasaka R, Koeda K, Wakabayashi G, Suzuki K. Molecular analysis of single isolated glands in gastric cancers and their surrounding gastric intestinal metaplastic mucosa. Oncol Rep. 2010;23(1):25–33. DOI: 10.3892/or_00000602.Li B, Liu HY, Guo SH, Sun P, Gong FM, Jia BQ. Detection of microsatellite instability in gastric cancer and dysplasia tissues. Int J Clin Exp Med. 2015;8(11):21442–21447. PMID: 26885089.Li B, Liu HY, Guo SH, Sun P, Gong FM, Jia BQ. Microsatellite instability of gastric cancer and precancerous lesions. Int J Clin Exp Med. 2015;8(11):21138–21144. PMID: 26885046.