Molecular classifications of gastric cancer and their clinical potential

   Gastric cancer if the 5^th most common oncological disease in the world and one of the leading causes of death associated with this pathology. In clinical practice, the Lauren classification is widely used for gastric cancer characterization, but it does not provide accurate information on tumor progression and does not allow to select the optimal therapeutic approach. More modern tumor typologies, for example proposed by the The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG), are based on profiling of molecular changes in the tumor genome. Currently, several new classifications exist dividing gastric cancer into groups depending on response to different treatment, for example, checkpoint inhibitors or therapy based on activity of pathological pathways associated with immunity, DNA repair, oncogenic and stromal signatures. The proposed typologies improve diagnosis and treatment of this pathology. The review describes currently available classifications of gastric tumors and considers their practical potential.

1. Ferlay J., Soerjomataram I., Dikshit R. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136(5):E359–86. DOI: 10.1002/ijc.29210

2. Japanese gastric cancer association japanese gastric cancer treatment guidelines 2018 (5^th edition). Gastric Cancer 2021;24(1):1–21. DOI: 10.1007/s10120-020-01042-y

3. Grabsch H.I., Tan P. Gastric cancer pathology and underlying molecular mechanisms. Dig Surg 2013;30(2):150–8. DOI: 10.1159/000350876

4. Hu B., El Hajj N., Sittler S. et al. Gastric cancer: classification, histology and application of molecular pathology. J Gastrointest Oncol 2012;3(3):251–61. DOI: 10.3978/j.issn.2078-6891.2012.021

5. Lin X., Zhao Y., Song W.-M., Zhang B. Molecular classification and prediction in gastric cancer. Comput Struct Biotechnol J 2015; 13:448–58. DOI: 10.1016/j.csbj.2015.08.001

6. Nemtsova M.V., Bure I.V., Zaletaev D.V. et al. Е-cadherin in gastric cancer tumorigenesis. Medicinskaya genetika = Medical Genetics 2022;21(5):3–17. (In Russ.). DOI: 10.25557/2073-7998.2022.05.3-17

7. Ma J., Shen H., Kapesa L., Zeng S. Lauren classification and individualized chemotherapy in gastric cancer. Oncol Lett 2016;11(5):2959–64. DOI: 10.3892/ol.2016.4337

8. Comprehensive Molecular Characterization of Gastric Adenocarcinoma. Nature 2014;513(7517):202–9. DOI: 10.1038/nature13480

9. Strand M.S., Lockhart A.C., Fields R.C. Genetics of gastric cancer. Surg Clin North Am 2017;97(2):345–70. DOI: 10.1016/j.suc.2016.11.009

10. Loeb L.A. A mutator phenotype in cancer. Cancer Res 2001;61(8):3230–9.

11. Kawakami H., Zaanan A., Sinicrope F.A. Microsatellite instability testing and its role in the management of colorectal cancer. Curr Treat Options Oncol 2015;16(7):30. DOI: 10.1007/s11864-015-0348-2

12. Naseem M., Barzi A., Brezden-Masley C. et al. Outlooks on Epstein–Barr virus associated gastric cancer. Cancer Treat Rev 2018;66:15–22. DOI: 10.1016/j.ctrv.2018.03.006

13. Sun K., Jia K., Lv H. et al. EBV-positive gastric cancer: current knowledge and future perspectives. Front Oncol 2020;10:583463. DOI: 10.3389/fonc.2020.583463

14. Zhao J., Liang Q., Cheung K.-F. et al. Genome-wide identification of Epstein–Barr virus-driven promoter methylation profiles of human genes in gastric cancer cells. Cancer 2013;119(2):304–12. DOI: 10.1002/cncr.27724

15. Wang J., Liu W., Zhang X. et al. LMP2A induces DNA methy-lation and expression repression of AQP3 in EBV-associated gastric carcinoma. Virology 2019;534:87–95. DOI: 10.1016/j.virol.2019.06.006

16. Ignatova E., Seriak D., Fedyanin M. et al. Epstein–Barr virus-associated gastric cancer: disease that requires special approach. Gastric Cancer 2020;23(6):951–60. DOI: 10.1007/s10120-020-01095-z

17. Geddert H., zur Hausen A., Gabbert H.E., Sarbia M. EBV-infection in cardiac and non-cardiac gastric adenocarcinomas is associated with promoter methylation of P16, P14 and APC, but not HMLH1. Cell Oncol (Dordr) 2011;34(3):209–14. DOI: 10.1007/s13402-011-0028-6

18. Koh J., Ock C.-Y., Kim J.W. et al. Clinicopathologic implications of immune classification by PD-L1 expression and CD8-positive tumor-infiltrating lymphocytes in stage II and III gastric cancer patients. Oncotarget 2017;8(16):26356–67. DOI: 10.18632/oncotarget.15465

19. Ratti M., Lampis A., Hahne J.C. et al. Microsatellite instability in gastric cancer: molecular bases, clinical perspectives, and new treatment approaches. Cell Mol Life Sci 2018;75(22):4151–62. DOI: 10.1007/s00018-018-2906-9

20. Chao J., Fuchs C.S., Shitara K. et al. Assessment of pembrolizumab therapy for the treatment of microsatellite instability-high gastric or gastroesophageal junction cancer among patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 clinical trials. JAMA Oncol 2021;7(6):895–902. DOI: 10.1001/jamaoncol.2021.0275

21. Smyth E.C., Wotherspoon A., Peckitt C. et al. Mismatch repair deficiency, microsatellite instability, and survival: an exploratory analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. JAMA Oncol 2017;3(9):1197–203. DOI: 10.1001/jamaoncol.2016.6762

22. Nam S., Kim J.H., Lee D.H. RHOA in gastric cancer: functional roles and therapeutic potential. Front Genet 2019;10:438. DOI: 10.3389/fgene.2019.00438

23. Ling Y., Watanabe Y., Nagahashi M. et al. Genetic profiling for diffuse type and genomically stable subtypes in gastric cancer. Comput Struct Biotechnol J 2020;18:3301–8. DOI: 10.1016/j.csbj.2020.10.021

24. Ma H., He Z., Chen J. et al. Identifying of biomarkers associated with gastric cancer based on 11 topological analysis methods of cytohubba. Sci Rep 2021;11(1):1331. DOI: 10.1038/s41598-020-79235-9

25. Zhang R., Liu Z., Chang X. et al. Clinical significance of chromosomal integrity in gastric cancers. Int J Biol Markers 2022;37(3): 296–305. DOI: 10.1177/03936155221106217

26. Cristescu R., Lee J., Nebozhyn M. 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

27. Buffart T.E., Louw M., van Grieken N.C.T. et al. Gastric cancers of Western European and African patients show different patterns of genomic instability. BMC Med Genomics 2011;4:7. DOI: 10.1186/1755-8794-4-7

28. Lin S.J., Gagnon-Bartsch J.A., Tan I.B. et al. Signatures of tumour immunity distinguish asian and non-asian gastric adenocarcinomas. Gut 2015;64(11):1721–31. DOI: 10.1136/gutjnl-2014-308252

29. Chia N.-Y., Tan P. Molecular classification of gastric cancer. Ann Oncol 2016;27(5):763–9. DOI: 10.1093/annonc/mdw040

30. Taube J.M., Klein A., Brahmer J.R. et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 2014;20(19):5064–74. DOI: 10.1158/1078-0432.CCR-13-3271

31. Le D.T., Uram J.N., Wang H. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372(26): 2509–20. DOI: 10.1056/NEJMoa1500596

32. Goodman A.M., Kato S., Bazhenova L. et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther 2017;16(11):2598–2608. DOI: 10.1158/1535-7163.MCT-17-0386

33. Jiang Z., Liu Z., Li M. et al. Immunogenomics analysis reveals that TP53 mutations inhibit tumor immunity in gastric cancer. Transl Oncol 2018;11(5):1171–87. DOI: 10.1016/j.tranon.2018.07.012

34. Li L., Wang X. Identification of gastric cancer subtypes based on pathway clustering. NPJ Precis Oncol 2021;5(1):46. DOI: 10.1038/s41698-021-00186-z

35. Lei Z., Tan I.B., Das K. et al. Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil. Gastroenterology 2013;145(3):554–65. DOI: 10.1053/j.gastro.2013.05.010

36. Cheong J.-H., Yang H.-K., Kim H. et al. Predictive test for chemotherapy response in resectable gastric cancer: a multi-cohort, retrospective analysis. Lancet Oncol 2018;19(5):629–38. DOI: 10.1016/S1470-2045(18)30108-6

37. Choi Y.Y., Jang E., Seo W.J. et al. Modification of the TNM staging system for stage II/III gastric cancer based on a prognostic single patient classifier algorithm. J Gastric Cancer 2018;18(2):142–51. DOI: 10.5230/jgc.2018.18.e14

38. Jeon J., Cheong J.-H. Clinical implementation of precision medicine in gastric cancer. J Gastric Cancer 2019;19(3):235–53. DOI: 10.5230/jgc.2019.19.e25