Microsatellite Instability in Chronic Gastritis Associated with Gastric Cancer
https://doi.org/10.22416/1382-4376-2025-35-4-48-59
Abstract
Aim: to assess the microsatellite instability status in gastric mucosa to determine the possibility of its use as a predictive marker of carcinogenesis.
Material and methods. The study included two groups of gastric mucosa specimens: Group 1 — 155 mucosa fragments of the distant tumor growth zone obtained from stomachs resected for malignant neoplasms; Group 2 — 100 fragments with chronic gastritis taken from patients with dyspeptic complaints. Gastrobiopsy specimens were examined histologically, immunohistochemically using mouse monoclonal antibodies (Diagnostic BioSystems, USA) to the MMR system proteins: MLH-1 (clone G168-15, dilution 1:50), MSH2 (clone DBM15.82, dilution 1:100), MSH6 (clone 44, dilution 1:50), PMS2 (clone A16-4, ready to use). MSI was studied with multiplex PCR evaluation of DNA microsatellites (NR-21, NR-24, NR-27, BAT-25, BAT-26) from paraffin sections, their analysis with capillary electrophoresis. The obtained data were processed with the Statistica 10.0 (StatSoft Inc., USA), presented using descriptive, analytical statistics.
Results. Immunohistochemical examination revealed 8 microsatellite-unstable cases in gastric mucosa specimens of Group 1 and 0 cases in Group 2 (statistically significant differences, p = 0.024). All studied gastric tissue samples were assessed as microsatellite-stable based on PCR results.
Conclusion. Detection of MMR deficiency in gastric mucosa of the distant tumor growth zone and its absence in morphologically comparable specimens obtained from patients with chronic gastritis may be considered as confirmation of the hypothesis of disturbances in the MMR system as an early event in carcinogenesis. This, in turn, may indicate the potential for studying MMR status as a component of a decision support system for assessing the risk of developing microsatellite-associated gastric cancer.
Keywords
About the Authors
A. V. KononovRussian Federation
Alexei V. Kononov — Dr. Sci. (Med.), Professor, Head of the Department
of Pathological Anatomy
644099, Omsk, Lenina str., 12
V. A. Rubtsov
Russian Federation
Vyacheslav A. Rubtsov — Сand. Sci. (Med.), Associate Professor at the Department of Pathological Anatomy
644099, Omsk, Lenina str., 12
E. V. Demidova
Russian Federation
Elizaveta V. Demidova — Сand. Sci. (Biol.), Junior Researcher, PCR Laboratory
630117, Novosibirsk-117, P.O. Box 492
M. N. Parygina
Russian Federation
Maria N. Parygina — Сand. Sci. (Med.), Teaching Assistant at the Department of Pathological Anatomy
644099, Omsk, Lenina str., 12
A. G. Shimanskaya
Russian Federation
Anna G. Shimanskaya — Сand. Sci. (Med.), Docent, Associate
Professor at the Department of Pathological Anatomy
644099, Omsk, Lenina str., 12
S. I. Mozgovoi
Russian Federation
Sergei I. Mozgovoi — Dr. Sci. (Med.), Docent, Professor
at the Department of Pathological Anatomy
644099, Omsk, Lenina str., 12
E. G. Pomorgailo
Russian Federation
Elena G. Pomorgailo — Dr. Sci. (Biol.), Docent, Professor
at the Department of Pathological Anatomy
644099, Omsk, Lenina str., 12
М. V. Markelova
Russian Federation
Marina V. Markelova — Сand. Sci. (Med.), Docent, Associate Professor at the Department of Pathological Anatomy
644099, Omsk, Lenina str., 12
References
1.
2. Luchini C., Bibeau F., Ligtenberg M.J.L., Singh N., Nottegar A., Bosse T., et al. 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):1232–43. DOI: 10.1093/annonc/mdz116
3. Yamamoto H., Watanabe Y., Arai H., Umemoto K., Tateishi K., Sunakawa Y. Microsatellite instability: A 2024 update. Cancer Sci. 2024;115(6):1738–48. DOI: 10.1111/cas.16160
4. Olave M.C., Graham R.P. Mismatch repair deficiency: The what, how and why it is important. Genes Chromosomes Cancer. 2022;61(6):314–21. DOI: 10.1002/gcc.23015
5. 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
6. Le D.T., Durham J.N., Smith K.N., Wang H., Bartlett B.R., Aulakh L.K., et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–13. DOI: 10.1126/science.aan6733
7. Le D.T., Uram J.N., Wang H., Bartlett B.R., Kemberling H., Eyring A.D., et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20. DOI: 10.1056/NEJMoa1500596
8. The WHO Classification of Tumours Editorial Board, eds. Digestive system tumours. WHO Classification of Tumours. 5th ed. IARC, 2019.
9. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202–9. DOI: 10.1038/nature13480
10. Cristescu R., Lee J., Nebozhyn M., Kim K.M., Ting J.C., Wong S.S., et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21(5):449–56. DOI: 10.1038/nm.3850
11. Danilova N.V., Chayka A.V., Khomyakov V.M., Oleynikova N.A., Andreeva Yu.Yu., Malkov P.G. Microsatellite instability in gastric cancer is a predictor of a favorable prognosis. Arkhiv Patologii. 2022;84(6):5–15. (In Russ.)]. DOI: 10.17116/patol2022840615
12. Ajani J.A., D’Amico T.A., Bentrem D.J., Chao J., Cooke D., Corvera C., et al. Gastric cancer, version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(2):167–92. DOI: 10.6004/jnccn.2022.0008
13. Kim J.-Y., Shin N.R., Kim A., Lee H.J., Park W.Y., Kim J.Y., et al. Microsatellite instability status in gastric cancer: A reappraisal of its clinical significance and relationship with mucin phenotypes. Korean J Pathol. 2013;47(1):28–35. DOI: 10.4132/KoreanJPathol.2013.47.1.28
14. Mathiak M., Warneke V.S., Behrens H.-M., Haag J., Böger C., Krüger S., et al. Clinicopathologic characteristics of microsatellite instable gastric carcinomas revisited: Urgent need for standardization. Appl Immunohistochem Mol Morphol. 2017;25(1):12–24. DOI: 10.1097/PAI.0000000000000264
15. Fang D.C., Jass J.R., Wang D.X., Zhou X.D., Luo Y.H., 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):504–8. DOI: 10.1136/jcp.52.7.504
16. Hamamoto T., Yokozaki H., Semba S., Yasui W., Yunotani S., Miyazaki K., et al. Altered microsatellites in incomplete-type intestinal metaplasia adjacent to primary gastric cancers. J Clin Pathol. 1997;50(10):841–6. DOI: 10.1136/jcp.50.10.841
17. 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):1113–9. DOI: 10.1016/s0959-8049(00)00066-6
18. Leung W.K., Kim J.J, Kim J.G., Graham D.Y., Sepulveda A.R. Microsatellite instability in gastric intestinal metaplasia in patients with and without gastric cancer. Am J Pathol. 2000;156(2):537–43. DOI: 10.1016/S0002-9440(10)64758-X
19. Garay J., Bravo J.C., Correa P., Schneider B.G. Infrequency of microsatellite instability in complete and incomplete gastric intestinal metaplasia. Hum Pathol. 2004;35(1):102–6. DOI: 10.1016/j.humpath.2003.08.023
20. Malfertheiner P., Megraud F., Rokkas T., Gisbert J.P., Liou J.M., Schulz C., et al.; European Helicobacter and Microbiota Study group. Management of Helicobacter pylori infection: The Maastricht VI/Florence consensus report. Gut. 2022. DOI: 10.1136/gutjnl-2022-327745
21. Parygina M.N., Pomorgailo E.G., Shimanskaya A.G., Panyushkin L.V., Mozgovoy S.I., Kononov A.V. A comparative assessment of technics for the orientation of gastric biopsy samples. Journal of New Medical Technologies. eEdition 2020;14(1):151–6. (In Russ.)]. DOI: 10.24411/2075-4094-2020-16588
22. Koo M., Squires J.M., Ying D., Huang J. Making a tissue microarray. Methods Mol Biol. 2019;1897:313–23. DOI: 10.1007/978-1-4939-8935-5_27
23. Dixon M.F., Genta R.M., Yardley J.H., Correa P. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol. 1996;20(10):1161–81. DOI: 10.1097/00000478-199610000-00001
24. 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
25. Luchini C., Bibeau F., Ligtenberg M.J.L., Singh N., Nottegar A., Bosse T., et al. 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):1232–43. DOI: 10.1093/annonc/mdz116
26. van der Werf-'t Lam A.S., Terlouw D., Tops C.M., van Kan M.S., van Hest L.P., Gille H.J.P., et al. Discordant staining patterns and microsatellite results in tumors of MSH6 pathogenic variant carriers. Mod Pathol. 2023;36(9):100240. DOI: 10.1016/j.modpat.2023.100240
27. Najjar Sadeghi R., Sahba N., Vahedi M., Reza Mohebbi S., Reza Zali M. Association of intron and exon polymorphisms of p53 gene in Iranian patients with gastritis. Gastroenterol Hepatol Bed Bench. 2013;6 (Suppl 1): S45–51.
Supplementary files
Review
For citations:
Kononov A.V., Rubtsov V.A., Demidova E.V., Parygina M.N., Shimanskaya A.G., Mozgovoi S.I., Pomorgailo E.G., Markelova М.V. Microsatellite Instability in Chronic Gastritis Associated with Gastric Cancer. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2025;35(4):48-59. https://doi.org/10.22416/1382-4376-2025-35-4-48-59