Research Article
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Expression patterns of eighteen genes involved in crucial cellular processes in the TP53 pathway in Multiple Myeloma

Year 2024, Volume: 37 Issue: 3, 1066 - 1082, 01.09.2024

Gözde Öztan , Ilknur Suer , Aynur Daglar Aday , Mesut Ayer , Şükrü Öztürk , Kıvanç Çefle , Mustafa Nuri Yenerel , Halim İşsever , Şükrü Palanduz

https://doi.org/10.35378/gujs.1365179

Abstract

Multiple myeloma (MM) is a malignant disease that causes abnormal immunoglobulin synthesis by bone marrow plasma cells. The relationship between MM and the TP53 pathway has not been fully elucidated in the literature. Investigation of the effect of the expression of genes in the TP53 pathway on the molecular pathogenesis and prognosis of multiple myeloma disease. We assessed the expression of 18 genes in the TP53 pathway in 48 MM patients and 31 healthy subjects by RT2-profiler PCR array technique, and investigated their possible association with the presence of cytogenetic aberrations. Twelve of the 18 genes (APAF1, ATM, BAX, CASP9, CDK4, CDKN1A, CDKN2A, E2F1, MCL1, MDM2, MDM4, PTEN) expression levels were found to be statistically up-regulated in MM patients compared to controls. The CDK4, CDKN1A and MCL1 genes were found to have remarkable diagnostic power distinguishing MM and healthy controls (AUC=0.89;AUC=0.86;AUC=0.77, respectively and p<0.001 for all three) via using Receiver operating characteristic (ROC) analysis. Overexpression of CDK4 and CDKN1A, which are involved in the cell cycle, and MCL1, which is an important gene in the anti-apoptotic process, were found to be excessively increased in MM patients compared to controls in terms of mRNA fold change. In addition, the high sensitivity of these genes found in the ROC analysis results suggests that they may be suggested as potential biomarkers for MM.

Keywords

Multiple myeloma TP53 pathway RT² Profiler PCR Array Gene expression

Ethical Statement

Ethical approval was obtained from the Istanbul Medical Faculty Clinical Research Ethic Committee (E-29624016-050.99-876968/May 9, 2022).

Supporting Institution

The authors received no extramural funding for the study.

References

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  • [20] Ge, S.X., Jung, D., Yao, R., "ShinyGO: a graphical gene-set enrichment tool for animals and plants", Bioinformatics, 36(8): 2628-2629, (2020).
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  • [35] Dilworth, D., Liu, L., Stewart, A.K., Berenson, J.R., Lassam, N., Hogg, D., "Germline CDKN2A mutation implicated in predisposition to multiple myeloma", Blood, The Journal of the American Society of Hematology, 95(5): 1869-1871, (2000).
  • [36] Zhan, F., Hardin, J., Kordsmeier, B., Bumm, K., Zheng, M., Tian, E., Sanderson, R., Yang, Y., Wilson, C., Zangari, M., Anaissie, E., Morris, C., Muwalla, F., van Rhee, F., Fassas, A., Crowley, J., Tricot, G., Barlogie, B., Shaughnessy, J., Jr., " Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells", Blood, 99(5): 1745-57, (2002).
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Year 2024, Volume: 37 Issue: 3, 1066 - 1082, 01.09.2024

Gözde Öztan , Ilknur Suer , Aynur Daglar Aday , Mesut Ayer , Şükrü Öztürk , Kıvanç Çefle , Mustafa Nuri Yenerel , Halim İşsever , Şükrü Palanduz

https://doi.org/10.35378/gujs.1365179

Abstract

References

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  • [2] Flynt, E., Bisht, K., Sridharan, V., Ortiz, M., Towfic, F., Thakurta, A., "Prognosis, Biology, and Targeting of TP53 Dysregulation in Multiple Myeloma", Cells, 9(2): 287, (2020).
  • [3] López-Corral, L., Corchete, L.A., Sarasquete, M.E., Mateos, M.V., García-Sanz, R., Fermiñán, E., Lahuerta, J.J., Bladé, J., Oriol, A., Teruel, A.I., Martino, M.L., Hernández, J., Hernández-Rivas, J.M., Burguillo, F.J., San Miguel, J.F., Gutiérrez, N.C., "Transcriptome analysis reveals molecular profiles associated with evolving steps of monoclonal gammopathies", Haematologica, 99(8): 1365-72, (2014).
  • [4] Levine, A.J., Carpten, J.D., Murphy, M., Hainaut, P., "Exploring the genetic and molecular basis of differences in multiple myeloma of individuals of African and European descent", Cell Death & Differentiation, 31: 1-8, (2024).
  • [5] Ye, F., Wang, T., Liu, A., Li, Y., Li, N., Wang, H., Chen, W., "Clinical Significance of TP53 Abnormalities in Newly Diagnosed Multiple Myeloma", Turkish Journal of Hematology, 38(4): 246-253, (2021).
  • [6] Herrero, A.B., Rojas, E.A., Misiewicz-Krzeminska, I., Krzeminski, P., Gutierrez, N.C., "Molecular Mechanisms of p53 Deregulation in Cancer: An Overview in Multiple Myeloma", International Journal of Molecular Sciences, 17(12): 2003, (2016).
  • [7] Stühmer, T., Chatterjee, M., Hildebrandt, M., Herrmann, P., Gollasch, H., Gerecke, C., Theurich, S., Cigliano, L., Manz, R.A., Daniel, P.T., Bommert, K., Vassilev, L.T., Bargou, R.C., "Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma", Blood, 106(10): b3609-17, (2005).
  • [8] Maes, A., Menu, E., Veirman, K., Maes, K., Vand Erkerken, K., De Bruyne, E., "The therapeutic potential of cell cycle targeting in multiple myeloma", Oncotarget, 8(52): 90501-90520, (2017).
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  • [11] Mateos, M.V., Ailawadhi, S., Costa, L.J., Grant, S.J., Kumar, L., Mohty, M., Aydin, D., Usmani, S.Z., "Global disparities in patients with multiple myeloma: a rapid evidence assessment", Blood Cancer Journal, 13(1): 109, (2023).
  • [12] Kazandjian, D., "Multiple myeloma epidemiology and survival: A unique malignancy", Seminars in Oncology, 43(6): 676-681, (2016).
  • [13] Öztan, G., Aktan, M., Palanduz, S., İşsever, H., Öztürk, S., Nikerel, E., Uçur, A., Bağatir, G., Bayrak, A., Çefle, K., "Relationship between Chromosomal Aberrations and Gene Expressions in the p53 Pathway in Chronic Lymphocytic Leukemia", Balkan Journal of Medical Genetics, 23(1): 15-24, (2020).
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  • [15] Gonzalez Garcia, J.R., Meza-Espinoza, J.P., "Use of the International System for Human Cytogenetic Nomenclature (ISCN)", Blood, 108(12): 3952-3, (2006).
  • [16] Szklarczyk, D., Gable, A.L., Nastou, K.C., Lyon, D., Kirsch, R., Pyysalo, S., Doncheva, N.T., Legeay, M., Fang, T., Bork, P., Jensen, L.J., von Mering, C., "The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets", Nucleic Acids Research, 49(D1): D605-D612, (2021).
  • [17] Szklarczyk, D., Morris, J.H., Cook, H., Kuhn, M., Wyder, S., Simonovic, M., Santos, A., Doncheva, N.T., Roth, A., Bork, P., Jensen, L.J., von Mering, C., "The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible", Nucleic Acids Research, 45(D1): D362-D368, (2017).
  • [18] Ashburner, M., Ball, C.A., Blake, J.A., Botstein, D.,Butler, H.,Cherry, J.M., Davis, A.P., Dolinski, K., Dwight, S.S., Eppig, J.T., Harris, M.A., Hill, D.P., Issel-Tarver, L., Kasarskis, A., Lewis, S., Matese, J.C., Richardson, J.E., Ringwald, M., Rubin, G.M., Sherlock, G., "Gene ontology: tool for the unification of biology. The Gene Ontology Consortium", Nature Genetics, 25(1): 25-9, (2000).
  • [19] Kopke, G, Anklam, K., Kulow, M., Baker, L., Swalve, H.H., Lopes, F.B., Rosa, G.J.M., Döpfer, D., "The identification of gene ontologies and candidate genes for digital dermatitis in beef cattle from a genomewide association study", International Journal of Veterinary Sciences Research, 6(1): 027-037, (2020).
  • [20] Ge, S.X., Jung, D., Yao, R., "ShinyGO: a graphical gene-set enrichment tool for animals and plants", Bioinformatics, 36(8): 2628-2629, (2020).
  • [21] Solimando, A.G., Da Vià, M.C., Bolli, N., Steinbrunn, T., "The route of the malignant plasma cell in its survival niche: Exploring “Multiple myelomas", Cancers, 14(13): 3271, (2022).
  • [22] Sadaf, H., Hong, H., Maqbool, M., Emhoff, K., Lin, J., Yan, S., Anwer, F., Zhao, J., "Multiple myeloma etiology and treatment", Journal of Translational Genetics and Genomics, 6(1): 63-83, (2022).
  • [23] Teoh, P.J., Chng, W.J., "p53 abnormalities and potential therapeutic targeting in multiple myeloma", BioMed research international, 2014: 717919, (2014).
  • [24] Puła, A., Robak, P., Mikulski, D., Robak, T., "The significance of mRNA in the biology of multiple myeloma and its clinical implications", International Journal of Molecular Sciences, 22(21): 12070, (2021).
  • [25] Drozdkova, D.H., Gursky, J., Minarik, J., Uberall, I., Kolar, Z., Trtkova, K.S., "CDKN1A Gene Expression in Two Multiple Myeloma Cell Lines With Different P53 Functionality", Anticancer Research, 40(9): 4979-4987, (2020).
  • [26] Ahmadi, S.E., Rahimi, S., Zarandi, B., Chegeni, R., Safa, M., "MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies", Journal of Hematology & Oncology, 14(1): 121, (2021).
  • [27] Fortin, A., Cregan, S.P., MacLaurin, J.G., Kushwaha, N., Hickman, E.S., Thompson, C.S., Hakim, A., Albert, P.R., Cecconi, F., Helin, K., Park, D.S., Slack, R.S., "APAF1 is a key transcriptional target for p53 in the regulation of neuronal cell death", Journal of Cell Biology, 155(2): 207-16, (2001).
  • [28] Lees, A., Sessler, T., McDade, S., "Dying to Survive-The p53 Paradox", Cancers (Basel), 13(13): 3257, (2021).
  • [29] Bansal, R., Rakshit, S., Han, W., Kumar, S.K., "Modulation of Apoptosis Pathways in the Biology and Treatment of Multiple Myeloma", Oncology & Haematology, 17(1): 48–54, (2021).
  • [30] Putzer, B.M., "Targeting E2F1 death signaling: opposing role in cancer control and neurodegeneration", Discovery Medicine, 6(33): 123-127, (2009).
  • [31] Teoh, G., Urashima, M., Ogata, A., Chauhan, D., DeCaprio, J.A., Treon, S.P., Schlossman, R.L., Anderson, K.C., "MDM2 protein overexpression promotes proliferation and survival of multiple myeloma cells", Blood, 90(5): 1982-92, (1997).
  • [32] Huang, X., Di Liberto, M., Louie, T., Jayabalan, D.S., Ely, S., Niesvizky, R., Chen-Kiang, S., "Selective Inhibition of CDK4 and CDK6 Primes Chemoresistant Myeloma Cell for Cytotoxic Killing through Induction of Cell Cycle-Coupled Mitochondrial Dysfunction and Apoptosis", Blood, 112(11): 3678, (2008).
  • [33] Renner, S., Weisz, J., Krajewski, S., Krajewska, M., Reed, J.C., Lichtenstein, A., "Expression of BAX in plasma cell dyscrasias", Clinical cancer research, 6(6): 2371-2380, (2000).
  • [34] Skrtic, A., Jaksic, O., Ostojic, S., Antica, M., Crnkovic, P., Skelin, J., Jurenec, S., Habijanec, B., Kristo, D.R., "Association between BCL2, BCL2 E17, MCL1 and BAX Protein Expression, Bone Marrow Microenvironment Histological Features, Clinical Presentation, Therapeutic Outcome, and the Overall Survival in Newly Diagnosed Multiple Myeloma", Blood, 138(1): 4716, (2021).
  • [35] Dilworth, D., Liu, L., Stewart, A.K., Berenson, J.R., Lassam, N., Hogg, D., "Germline CDKN2A mutation implicated in predisposition to multiple myeloma", Blood, The Journal of the American Society of Hematology, 95(5): 1869-1871, (2000).
  • [36] Zhan, F., Hardin, J., Kordsmeier, B., Bumm, K., Zheng, M., Tian, E., Sanderson, R., Yang, Y., Wilson, C., Zangari, M., Anaissie, E., Morris, C., Muwalla, F., van Rhee, F., Fassas, A., Crowley, J., Tricot, G., Barlogie, B., Shaughnessy, J., Jr., " Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells", Blood, 99(5): 1745-57, (2002).
  • [37] Katiyar, A., Kaur, G., Rani, L., Jena, L., Singh, H., Kumar, L., Sharma, A., Kaur, P., Gupta, R., "Genome-wide identification of potential biomarkers in multiple myeloma using meta-analysis of mRNA and miRNA expression data", Scientific Reports, 11(1): 10957, (2021).
  • [38] Wei, A.H., Roberts, A.W., Spencer, A., Rosenberg, A.S., Siegel, D., Walter, R.B., Caenepeel, S., Hughes, P., McIver, Z., Mezzi, K., Morrow, P.K., Stein, A., "Targeting MCL-1 in hematologic malignancies: Rationale and progress", Blood Reviews, 44: 100672, (2020).
  • [39] Adamia, S.Bhatt, S.Wen, K.Chyra, Z.Fell, G.G.Tai, Y.T.Pioso, M.S.Abiatari, I.Letai, A.Dorfman, D.M.Hideshima, T. Anderson, K.C.," Combination therapy targeting Erk1/2 and CDK4/6i in relapsed refractory multiple myeloma", Leukemia, 36(4): 1088-1101, (2022).
  • [40] Ozaki, T., Nakagawara, A., "Role of p53 in Cell Death and Human Cancers", Cancers (Basel), 3(1): 994-1013, (2011).
There are 40 citations in total.

Details

Primary Language English
Subjects Biological Network Analysis, Gene Expression
Journal Section Biology
Authors

Gözde Öztan 0000-0002-2970-1834

Ilknur Suer 0000-0003-1954-4190

Aynur Daglar Aday 0000-0001-8072-0646

Mesut Ayer 0000-0003-1977-0104

Şükrü Öztürk 0000-0002-8809-7462

Kıvanç Çefle 0000-0002-9420-4543

Mustafa Nuri Yenerel 0000-0002-6473-1342

Halim İşsever 0000-0002-5435-706X

Şükrü Palanduz 0000-0002-9435-009X

Early Pub Date April 2, 2024
Publication Date September 1, 2024
Published in Issue Year 2024 Volume: 37 Issue: 3

Cite

APA Öztan, G., Suer, I., Daglar Aday, A., Ayer, M., et al. (2024). Expression patterns of eighteen genes involved in crucial cellular processes in the TP53 pathway in Multiple Myeloma. Gazi University Journal of Science, 37(3), 1066-1082. https://doi.org/10.35378/gujs.1365179
AMA Öztan G, Suer I, Daglar Aday A, Ayer M, Öztürk Ş, Çefle K, Yenerel MN, İşsever H, Palanduz Ş. Expression patterns of eighteen genes involved in crucial cellular processes in the TP53 pathway in Multiple Myeloma. Gazi University Journal of Science. September 2024;37(3):1066-1082. doi:10.35378/gujs.1365179
Chicago Öztan, Gözde, Ilknur Suer, Aynur Daglar Aday, Mesut Ayer, Şükrü Öztürk, Kıvanç Çefle, Mustafa Nuri Yenerel, Halim İşsever, and Şükrü Palanduz. “Expression Patterns of Eighteen Genes Involved in Crucial Cellular Processes in the TP53 Pathway in Multiple Myeloma”. Gazi University Journal of Science 37, no. 3 (September 2024): 1066-82. https://doi.org/10.35378/gujs.1365179.
EndNote Öztan G, Suer I, Daglar Aday A, Ayer M, Öztürk Ş, Çefle K, Yenerel MN, İşsever H, Palanduz Ş (September 1, 2024) Expression patterns of eighteen genes involved in crucial cellular processes in the TP53 pathway in Multiple Myeloma. Gazi University Journal of Science 37 3 1066–1082.
IEEE G. Öztan, I. Suer, A. Daglar Aday, M. Ayer, Ş. Öztürk, K. Çefle, M. N. Yenerel, H. İşsever, and Ş. Palanduz, “Expression patterns of eighteen genes involved in crucial cellular processes in the TP53 pathway in Multiple Myeloma”, Gazi University Journal of Science, vol. 37, no. 3, pp. 1066–1082, 2024, doi: 10.35378/gujs.1365179.
ISNAD Öztan, Gözde et al. “Expression Patterns of Eighteen Genes Involved in Crucial Cellular Processes in the TP53 Pathway in Multiple Myeloma”. Gazi University Journal of Science 37/3 (September 2024), 1066-1082. https://doi.org/10.35378/gujs.1365179.
JAMA Öztan G, Suer I, Daglar Aday A, Ayer M, Öztürk Ş, Çefle K, Yenerel MN, İşsever H, Palanduz Ş. Expression patterns of eighteen genes involved in crucial cellular processes in the TP53 pathway in Multiple Myeloma. Gazi University Journal of Science. 2024;37:1066–1082.
MLA Öztan, Gözde et al. “Expression Patterns of Eighteen Genes Involved in Crucial Cellular Processes in the TP53 Pathway in Multiple Myeloma”. Gazi University Journal of Science, vol. 37, no. 3, 2024, pp. 1066-82, doi:10.35378/gujs.1365179.
Vancouver Öztan G, Suer I, Daglar Aday A, Ayer M, Öztürk Ş, Çefle K, Yenerel MN, İşsever H, Palanduz Ş. Expression patterns of eighteen genes involved in crucial cellular processes in the TP53 pathway in Multiple Myeloma. Gazi University Journal of Science. 2024;37(3):1066-82.