Chromosomal instability in gastric cancer

The Cancer Genome Atlas (TCGA), using approaches based on the analysis of full-exome sequencing, changes in the copy of chromosomal loci, gene expression, DNA methylation and protein activity, proposed a molecular classification of gastric cancer into four subtypes: the subtype associated with Epstein-Barr virus (EBV+), the subtype associated with microsatellite instability (MSI), chromosomally unstable subtype (CIN) and genomically stable subtype (GS). However, the subtype of GC with chromosomal instability is still insufficiently described and does not have effective and convenient markers for diagnosis, molecular and histological verification. The CIN subtype of GC is characterized by the presence of chromosomal instability, which is manifested by an increased frequency of aneuploidies and/or structural chromosomal rearrangements in tumor cells. Structural rearrangements in CIN subtype of GC are not accidental and are detected in certain chromosomal loci, which are often subject to rearrangements as a result of a certain structural organization. The review considers the molecular mechanisms and possible causes leading to the appearance of chromosomal instability in GC, presents the common rearrangements of chromosomal loci and their impact on the development and clinical course of the disease, as well as lists the driver genes, their functions and the possibilities of targeting them in CIN subtype of GC. 

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: E359-386, doi:10.1002/ijc.29210.

2. Japanese Gastric Cancer Association Japanese Gastric Cancer Treatment Guidelines 2018 (5th Edition). Gastric Cancer. 2021; 24: 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: 150–158, doi:10.1159/000350876.

4. Hu B., El Hajj N., Sittler S., Lammert N., Barnes R., Meloni-Ehrig A. Gastric Cancer: Classification, Histology and Application of Molecular Pathology. J Gastrointest Oncol. 2012; 3: 251–261, 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: 448–458, doi:10.1016/j.csbj.2015.08.001.

6. McCracken K.W., Aihara E., Martin B., et al.. Wnt/β-Catenin Promotes Gastric Fundus Specification in Mice and Humans. Nature. 2017; 541: 182–187, doi:10.1038/nature21021.

7. Ma J., Shen H., Kapesa L., Zeng S. Lauren Classification and Individualized Chemotherapy in Gastric Cancer. Oncol Lett. 2016; 11: 2959–2964, doi:10.3892/ol.2016.4337.

8. Cancer Genome Atlas Research Network Comprehensive Molecular Characterization of Gastric Adenocarcinoma. Nature. 2014; 513: 202– 209, doi:10.1038/nature13480.

9. Strand M.S., Lockhart A.C., Fields R.C. Genetics of Gastric Cancer. Surg Clin North Am. 2017; 97: 345–370, doi:10.1016/j.suc.2016.11.009.

10. Geigl J.B., Obenauf A.C., Schwarzbraun T., Speicher M.R. Defining “Chromosomal Instability.” Trends Genet. 2008; 24: 64–69, doi:10.1016/j.tig.2007.11.006.

11. Loeb L.A. A Mutator Phenotype in Cancer. Cancer Res. 2001; 61: 3230–3239.

12. 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: 30, doi:10.1007/s11864-015-0348-2.

13. Maleki S.S., Röcken C. Chromosomal Instability in Gastric Cancer Biology. Neoplasia. 2017; 19: 412–420, doi:10.1016/j.neo.2017.02.012.

14. Sansregret L., Vanhaesebroeck B., Swanton C. Determinants and Clinical Implications of Chromosomal Instability in Cancer. Nat Rev Clin Oncol. 2018; 15: 139–150, doi:10.1038/nrclinonc.2017.198.

15. Holland A.J., Cleveland D.W. Boveri Revisited: Chromosomal Instability, Aneuploidy and Tumorigenesis. Nat Rev Mol Cell Biol. 2009; 10: 478–487, doi:10.1038/nrm2718.

16. Roy A., Cowan G., Mead A.J., et al. Perturbation of Fetal Liver Hematopoietic Stem and Progenitor Cell Development by Trisomy 21. Proc Natl Acad Sci U S A. 2012; 109: 17579–17584, doi:10.1073/pnas.1211405109.

17. Castellanos G., Valbuena D.S., Pérez E., Villegas V.E., Rondón-Lagos M. Chromosomal Instability as Enabling Feature and Central Hallmark of Breast Cancer. Breast Cancer (Dove Med Press). 2023; 15: 189–211, doi:10.2147/BCTT.S383759.

18. Wilhelm T., Said M., Naim V. DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons. Genes (Basel). 2020; 11: 642, doi:10.3390/genes11060642.

19. Gregan J., Polakova S., Zhang L., Tolić-Nørrelykke I.M., Cimini D. Merotelic Kinetochore Attachment: Causes and Effects. Trends Cell Biol. 2011; 21: 374–381, doi:10.1016/j.tcb.2011.01.003.

20. Ma H., He Z., Chen J., Zhang X., Song P. Identifying of Biomarkers Associated with Gastric Cancer Based on 11 Topological Analysis Methods of CytoHubba. Sci Rep. 2021; 11: 1331, doi:10.1038/s41598- 020-79235-9.

21. Mazouzi A., Velimezi G., Loizou J.I. DNA Replication Stress: Causes, Resolution and Disease. Exp Cell Res. 2014; 329: 85–93, doi:10.1016/j.yexcr.2014.09.030.

22. Cortez D. Replication-Coupled DNA Repair. Mol Cell. 2019; 74: 866–876, doi:10.1016/j.molcel.2019.04.027.

23. Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022; 12: 31–46, doi:10.1158/2159-8290.CD-21-1059.

24. Chen M., Linstra R., van Vugt M.A.T.M. Genomic Instability, Inflammatory Signaling and Response to Cancer Immunotherapy. Biochim Biophys Acta Rev Cancer. 2022; 1877: 188661, doi:10.1016/j.bbcan.2021.188661.

25. Wu C.-E., Yeh D.-W., Pan Y.-R. et al. Chromosomal Instability May Not Be a Predictor for Immune Checkpoint Inhibitors from a Comprehensive Bioinformatics Analysis. Life (Basel). 2020; 10: 276, doi:10.3390/life10110276.

26. Denko N.C., Giaccia A.J., Stringer J.R., Stambrook P.J. The Human Ha-Ras Oncogene Induces Genomic Instability in Murine Fibroblasts within One Cell Cycle. Proc Natl Acad Sci U S A. 1994; 91: 5124–5128, doi:10.1073/pnas.91.11.5124.

27. Blanchet A., Bourgmayer A., Kurtz J.-E., Mellitzer G., Gaiddon C. Isoforms of the P53 Family and Gastric Cancer: A Ménage à Trois for an Unfinished Affair. Cancers (Basel). 2021; 13: 916, doi:10.3390/ cancers13040916.

28. Rasnick D., Duesberg P.H. How Aneuploidy Affects Metabolic Control and Causes Cancer. Biochem J. 1999; 340 ( Pt 3): 621–630.

29. Cahill D.P., Lengauer C., Yu J., et al. Mutations of Mitotic Checkpoint Genes in Human Cancers. Nature. 1998; 392: 300–303, doi:10.1038/32688.

30. Li G.-S., Chen G., Liu J., et al. Clinical Significance of CyclinDependent Kinase Inhibitor 2C Expression in Cancers: From Small Cell Lung Carcinoma to Pan-Cancers. BMC Pulm Med. 2022; 22: 246, doi:10.1186/s12890-022-02036-5.

31. Bibi F., Ali I., Naseer M.I., et al. Detection of Genetic Alterations in Gastric Cancer Patients from Saudi Arabia Using Comparative Genomic Hybridization (CGH). PLoS One. 2018; 13: e0202576, doi:10.1371/journal.pone.0202576.

32. Ezaki T., Yanagisawa A., Ohta K., et al. Deletion Mapping on Chromosome 1p in Well-Differentiated Gastric Cancer. Br J Cancer. 1996; 73: 424–428, doi:10.1038/bjc.1996.76.

33. Barone G., Staples C.J., Ganesh A., et al. Human CDK18 Promotes Replication Stress Signaling and Genome Stability. Nucleic Acids Res. 2016; 44: 8772–8785, doi:10.1093/nar/gkw615.

34. Kim Y.-I., Pecha R.L., Keihanian T., et al. MUC1 Expressions and Its Prognostic Values in US Gastric Cancer Patients. Cancers (Basel). 2023; 15: 998, doi:10.3390/cancers15040998.

35. Buffart T.E., Carvalho B., Mons T., et al. DNA Copy Number Profiles of Gastric Cancer Precursor Lesions. BMC Genomics. 2007; 8: 345, doi:10.1186/1471-2164-8-345.

36. Morin P.J., Sparks A.B., Korinek V., et al. Activation of BetaCatenin-Tcf Signaling in Colon Cancer by Mutations in Beta-Catenin or APC. Science. 1997; 275: 1787–1790, doi:10.1126/ science.275.5307.1787.

37. Wistuba I.I., Maitra A., Carrasco R., et al. High Resolution Chromosome 3p, 8p, 9q and 22q Allelotyping Analysis in the Pathogenesis of Gallbladder Carcinoma. Br J Cancer. 2002; 87: 432– 440, doi:10.1038/sj.bjc.6600490.

38. Buffart T.E., Carvalho B., van Grieken N.C.T., et al. Losses of Chromosome 5q and 14q Are Associated with Favorable Clinical Outcome of Patients with Gastric Cancer. Oncologist. 2012; 17: 653– 662, doi:10.1634/theoncologist.2010-0379.

39. Dong Y., Tu R., Liu H., Qing G. Regulation of Cancer Cell Metabolism: Oncogenic MYC in the Driver’s Seat. Signal Transduct Target Ther. 2020; 5: 124, doi:10.1038/s41392-020-00235-2.

40. de Manzoni G., Tomezzoli A., Di Leo A., Moore P.S., Talamini G., Scarpa A. Clinical Significance of Mutator Phenotype and Chromosome 17p and 18q Allelic Loss in Gastric Cancer. Br J Surg. 2001; 88: 419–425, doi:10.1046/j.1365-2168.2001.01667.x.

41. Zhang R., Liu Z., Chang X., et al. Clinical Significance of Chromosomal Integrity in Gastric Cancers. Int J Biol Markers. 2022; 37: 296–305, doi:10.1177/03936155221106217.

42. Inoue T., Uchino S., Shiraishi N., Adachi Y., Kitano S. Loss of Heterozygosity on Chromosome 18q in Cohesive-Type Gastric Cancer Is Associated with Tumor Progression and Poor Prognosis. Clin Cancer Res. 1998; 4: 973–977.

43. Snijders A.M., Mao J.-H. Multi-Omics Approach to Infer Cancer Therapeutic Targets on Chromosome 20q across Tumor Types. Adv Mod Oncol Res. 2016; 2: 215–223, doi:10.18282/amor.v2.i4.141.

44. Ptashkin R.N., Pagan C., Yaeger R., et al. Chromosome 20q Amplification Defines a Subtype of Microsatellite Stable, Left-Sided Colon Cancers with Wild-Type RAS/RAF and Better Overall Survival. Mol Cancer Res. 2017; 15: 708–713, doi:10.1158/1541-7786.MCR-16-0352.

45. Gong P., Xu Y., Liu M., et al. Upregulation of LINC00659 Expression Predicts a Poor Prognosis and Promotes Migration and Invasion of Gastric Cancer Cells. Oncol Lett. 2021; 22: 557, doi:10.3892/ol.2021.12818.

46. de Mello R.A., Marques A.M., Araújo A. HER2 Therapies and Gastric Cancer: A Step Forward. World J Gastroenterol. 2013; 19: 6165–6169, doi:10.3748/wjg.v19.i37.6165.

47. Tabach Y., Kogan-Sakin I., Buganim Y., et al. Amplification of the 20q Chromosomal Arm Occurs Early in Tumorigenic Transformation and May Initiate Cancer. PLoS One. 2011; 6: e14632, doi:10.1371/journal.pone.0014632.

48. Cristescu R., Lee J., Nebozhyn M., et al. Molecular Analysis of Gastric Cancer Identifies Subtypes Associated with Distinct Clinical Outcomes. Nat Med. 2015; 21: 449–456, doi:10.1038/nm.3850.

49. Kastenhuber E.R., Lowe S.W. Putting P53 in Context. Cell. 2017; 170: 1062–1078, doi:10.1016/j.cell.2017.08.028.

50. Soussi T., Wiman K.G. TP53: An Oncogene in Disguise. Cell Death Differ. 2015; 22: 1239–1249, doi:10.1038/cdd.2015.53.

51. Frum R.A., Grossman S.R. Mechanisms of Mutant P53 Stabilization in Cancer. Subcell Biochem. 2014; 85: 187–197, doi:10.1007/978-94- 017-9211-0_10.

52. Li Q., Zhang L., Jiang J., et al. CDK1 and CCNB1 as Potential Diagnostic Markers of Rhabdomyosarcoma: Validation Following Bioinformatics Analysis. BMC Med Genomics. 2019; 12: 198, doi:10.1186/s12920-019-0645-x.

53. Li B., Zhu H.-B., Song G.-D., et al. Regulating the CCNB1 Gene Can Affect Cell Proliferation and Apoptosis in Pituitary Adenomas and Activate Epithelial-to-Mesenchymal Transition. Oncol Lett. 2019; 18: 4651–4658, doi:10.3892/ol.2019.10847.

54. Izadi S., Nikkhoo A., Hojjat-Farsangi M., et al. CDK1 in Breast Cancer: Implications for Theranostic Potential. Anticancer Agents Med Chem. 2020; 20: 758–767, doi:10.2174/1871520620666200203125712.

55. Zhang X., Ma H., Zou Q., Wu J. Analysis of Cyclin-Dependent Kinase 1 as an Independent Prognostic Factor for Gastric Cancer Based on Statistical Methods. Front Cell Dev Biol. 2020; 8: 620164, doi:10.3389/fcell.2020.620164.

56. Sofi S., Mehraj U., Qayoom H., et al. ;Cyclin-Dependent Kinases in Breast Cancer: Expression Pattern and Therapeutic Implications. Med Oncol. 2022; 39: 106, doi:10.1007/s12032-022-01731-x.

57. Yasukawa M., Ando Y., Yamashita T., et al. CDK1 Dependent Phosphorylation of HTERT Contributes to Cancer Progression. Nat Commun. 2020; 11: 1557, doi:10.1038/s41467-020-15289-7.

58. Huang X., Huang Q., Chen S., et al. Efficacy of Laparoscopic Adenomyomectomy Using Double-Flap Method for Diffuse Uterine Adenomyosis. BMC Womens Health. 2015; 15: 24, doi:10.1186/s12905-015-0182-5.

59. Huang S., Ye H., Guo W., et al. CDK4/6 Inhibitor Suppresses Gastric Cancer with CDKN2A Mutation. Int J Clin Exp Med. 2015; 8: 11692–11700.

60. Zhang M., Zhang L., Hei R., et al. CDK Inhibitors in Cancer Therapy, an Overview of Recent Development. Am J Cancer Res. 2021; 11: 1913–1935.

61. Sofi S., Mehraj U., Qayoom H., et al. Targeting Cyclin-Dependent Kinase 1 (CDK1) in Cancer: Molecular Docking and Dynamic Simulations of Potential CDK1 Inhibitors. Med Oncol. 2022; 39: 133, doi:10.1007/s12032-022-01748-2.

62. Giet R., Prigent C. Aurora/Ipl1p-Related Kinases, a New Oncogenic Family of Mitotic Serine-Threonine Kinases. J Cell Sci. 1999; 112 ( Pt 21): 3591–3601, doi:10.1242/jcs.112.21.3591.

63. Bischoff J.R., Plowman G.D. The Aurora/Ipl1p Kinase Family: Regulators of Chromosome Segregation and Cytokinesis. Trends Cell Biol. 1999; 9: 454–459, doi:10.1016/s0962-8924(99)01658-x.

64. Du R., Huang C., Liu K., Li X., Dong Z. Targeting AURKA in Cancer: Molecular Mechanisms and Opportunities for Cancer Therapy. Mol Cancer. 2021; 20: 15, doi:10.1186/s12943-020-01305-3.

65. Crosio C., Fimia G.M., Loury R., et al. Mitotic Phosphorylation of Histone H3: Spatio-Temporal Regulation by Mammalian Aurora Kinases. Mol Cell Biol. 2002; 22: 874–885, doi:10.1128/MCB.22.3.874-885.2002.

66. LeRoy P.J., Hunter J.J., Hoar K.M., et al. Localization of Human TACC3 to Mitotic Spindles Is Mediated by Phosphorylation on Ser558 by Aurora A: A Novel Pharmacodynamic Method for Measuring Aurora A Activity. Cancer Res. 2007; 67: 5362–5370, doi:10.1158/0008-5472.CAN-07-0122.

67. Chou E.-J., Hung L.-Y., Tang C.-J.C., et al. Phosphorylation of CPAP by Aurora-A Maintains Spindle Pole Integrity during Mitosis. Cell Rep. 2016; 14: 2975–2987, doi:10.1016/j.celrep.2016.02.085.

68. Venoux M., Basbous J., Berthenet C., et al. ASAP Is a Novel Substrate of the Oncogenic Mitotic Kinase Aurora-A: Phosphorylation on Ser625 Is Essential to Spindle Formation and Mitosis. Hum Mol Genet. 2008; 17: 215–224, doi:10.1093/hmg/ddm298.

69. Fu J., Bian M., Xin G., et al. TPX2 Phosphorylation Maintains Metaphase Spindle Length by Regulating Microtubule Flux. J Cell Biol. 2015; 210: 373–383, doi:10.1083/jcb.201412109.

70. Macůrek L., Lindqvist A., Lim D., et al. Polo-like Kinase-1 Is Activated by Aurora A to Promote Checkpoint Recovery. Nature. 2008; 455: 119–123, doi:10.1038/nature07185.

71. Dutertre S., Cazales M., Quaranta M., et al. Phosphorylation of CDC25B by Aurora-A at the Centrosome Contributes to the G2-M Transition. J Cell Sci. 2004; 117: 2523–2531, doi:10.1242/jcs.01108.

72. Dar A.A., Belkhiri A., El-Rifai W. The Aurora Kinase A Regulates GSK-3beta in Gastric Cancer Cells. Oncogene. 2009; 28: 866–875, doi:10.1038/onc.2008.434.

73. Katayama H., Sasai K., Kawai H., et al. Phosphorylation by Aurora Kinase A Induces Mdm2-Mediated Destabilization and Inhibition of P53. Nat Genet. 2004; 36: 55–62, doi:10.1038/ng1279.

74. Liu M., Li Y., Zhang C., Zhang Q. Role of Aurora Kinase B in Regulating Resistance to Paclitaxel in Breast Cancer Cells. Hum Cell. 2022; 35: 678–693, doi:10.1007/s13577-022-00675-8.

75. Nie M., Wang Y., Yu Z., et al. AURKB Promotes Gastric Cancer Progression via Activation of CCND1 Expression. Aging (Albany NY). 2020; 12: 1304–1321, doi:10.18632/aging.102684.

76. Wang Z., Yu Z., Wang G.-H., et al. AURKB Promotes the Metastasis of Gastric Cancer, Possibly by Inducing EMT. Cancer Manag Res. 2020; 12: 6947–6958, doi:10.2147/CMAR.S254250.

77. Tang A., Gao K., Chu L., Zhang R., Yang J., Zheng J. Aurora Kinases: Novel Therapy Targets in Cancers. Oncotarget. 2017; 8: 23937–23954, doi:10.18632/oncotarget.14893.

78. Kanayama K., Imai H., Usugi E., Shiraishi T., Hirokawa Y.S., Watanabe M. Association of HER2 Gene Amplification and Tumor Progression in Early Gastric Cancer. Virchows Arch. 2018; 473: 559– 565, doi:10.1007/s00428-018-2433-y.

79. Neve R.M., Lane H.A., Hynes N.E. The Role of Overexpressed HER2 in Transformation. Ann Oncol. 2001; 12( Suppl 1): S9-13, doi:10.1093/annonc/12.suppl_1.s9.

80. Dang H.-Z., Yu Y., Jiao S.-C. Prognosis of HER2 Over-Expressing Gastric Cancer Patients with Liver Metastasis. World J Gastroenterol. 2012; 18: 2402–2407, doi:10.3748/wjg.v18.i19.2402.

81. Shitara K., Bang Y.-J., Iwasa S., et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med. 2020; 382: 2419–2430, doi:10.1056/NEJMoa2004413.

82. Cai H., Jing C., Chang X., et al. Mutational Landscape of Gastric Cancer and Clinical Application of Genomic Profiling Based on Target Next-Generation Sequencing. J Transl Med. 2019; 17: 189, doi:10.1186/s12967-019-1941-0.

83. Díaz Del Arco C., Estrada Muñoz L., Molina Roldán E., et al. Immunohistochemical Classification of Gastric Cancer Based on New Molecular Biomarkers: A Potential Predictor of Survival. Virchows Arch. 2018; 473: 687–695, doi:10.1007/s00428-018-2443-9.

84. Tsai J.-H., Jeng Y.-M., Chen K.-H., Lee C.-H., Yuan C.-T., Liau J.-Y. An Integrative Morphomolecular Classification System of Gastric Carcinoma With Distinct Clinical Outcomes. Am J Surg Pathol. 2020; 44: 1017–1030, doi:10.1097/PAS.0000000000001521.

85. Silva A.N.S., Saito Y., Yoshikawa T., et al. Increasing Frequency of Gene Copy Number Aberrations Is Associated with Immunosuppression and Predicts Poor Prognosis in Gastric Adenocarcinoma. Br J Surg. 2022; 109: 291–297, doi:10.1093/bjs/znab460.

86. Wang W., Zhang Y., Chen R., et al. Chromosomal Instability and Acquired Drug Resistance in Multiple Myeloma. Oncotarget. 2017; 8: 78234–78244, doi:10.18632/oncotarget.20829.

87. Kohlruss M., Krenauer M., Grosser B., et al. Diverse “just-Right” Levels of Chromosomal Instability and Their Clinical Implications in Neoadjuvant Treated Gastric Cancer. Br J Cancer. 2021; 125: 1621– 1631, doi:10.1038/s41416-021-01587-4.