Gene Expression Profiling to Predict Prognostic Biomarkers for Relapse in Multiple Myeloma
Abstract
Background: Multiple myeloma (MM), an incurable malignancy of plasma cells (PCs), is the second most common hematological cancer caused primarily by structural variations (chromosomal aberrations and somatic mutations). The majority of the patients acquired resistance against standard therapeutic approaches for MM and experienced relapse despite the continuous advances in MM therapies.
Methods: We performed Differential Gene Expression (DGE), literature mining and SNV analysis of Next Generation Sequencing (NGS) data of Newly Diagnosed MM (NDMM) and Relapsed/Refractory MM (RRMM). The selected Differentially Expressed Genes (DEGs) were subjected to functional enrichment and pathway analysis. Immune cells infiltration analysis was also performed to estimate immune cells variations in the Tumor Microenvironment (TME) of RRMM.
Result: CSF1R, VCAN, NRP1, COL22A1, BPI, BIRC5, MNX1, FAT1, ERG, TCL1A, AFF3 were selected after DGE, literature mining and SNV analysis. The functional enrichment of these DEGs showed significant enrichment for positive regulation of cell population proliferation, serene/threonine kinase activity, endothelial cell proliferation, cytokine binding, G protein activity and GDP binding, whereas KEGG pathway analysis revealed vital role of PI3K-Akt signaling pathway along with various cancer pathways. The immune cells infiltration analysis revealed the higher count of neutrophils and lesser level of T cells (CD8+) in TME of RRMM.
Conclusion: Our study suggests that neutrophils play an important role in modulation of TME in RRMM. The selected DEGs have previously been identified in progression, drug resistance and relapse of various cancers. The role of these biomarkers in RRMM has not been explored yet. Therefore, neutrophils, selected DEGs and PI3K-Akt signaling pathway are potential targets to investigate in RRMM.
Keywords: Multiple Myeloma; Relapse; Differential Expression; Immune Cell Infiltration; Literature Mining
Full Text:
PDFReferences
Palumbo A, Anderson K. Multiple Myeloma. The New England journal of medicine, (2011); 364(11): 1046-1060.
Robert A Kyle MAG, Thomas E Witzig, John A Lust, Martha Q Lacy, Angela Dispenzieri, Rafael Fonseca, S Vincent Rajkumar, Janice R Offord, Dirk R Larson, Matthew E Plevak, Terry M Therneau, Philip R Greipp. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clinic Proceeding, (2003); 78(1): 21-33.
Rajkumar SV. Multiple myeloma: 2022 update on diagnosis, risk stratification, and management. American journal of hematology, (2022); 97(8): 1086-1107.
Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, et al. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, (2015); 33(26): 2863-2869.
Humaira Sadaf HH, Mohsin Maqbool, Kylin Emhoff, Jianhong Lin, Shan Yan, Faiz Anwer ,Jianjun Zhao. Multiple myeloma etiology and treatment. Journal of Translational Genetics and Genomics, ( 2022); 663-83.
Maura F, Bolli N, Angelopoulos N, Dawson KJ, Leongamornlert D, et al. Genomic landscape and chronological reconstruction of driver events in multiple myeloma. Nature communications, (2019); 10(1): 3835.
Chaimaa Saadoune BN, Hasna Hamdaoui, Fatima Chegdani, and Faiza Bennis. Multiple Myeloma: Bioinformatic Analysis for Identification of Key Genes and Pathways. Bioinformatics and Biology Insights, (2022); 16: 11779322221115545.
Nijhof IS, van de Donk N, Zweegman S, Lokhorst HM. Current and New Therapeutic Strategies for Relapsed and Refractory Multiple Myeloma: An Update. Drugs, (2018); 78(1): 19-37.
Chen C, Li Y, Miao P, Xu Y, Xie Y, et al. Tumor immune cell infiltration score based model predicts prognosis in multiple myeloma. Scientific reports, (2022); 12(1): 17082.
Pinto V, Bergantim R, Caires HR, Seca H, Guimaraes JE, et al. Multiple Myeloma: Available Therapies and Causes of Drug Resistance. Cancers, (2020); 12(2): 407.
Stratmann S, Vesterlund M, Umer HM, Eshtad S, Skaftason A, et al. Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children. Leukemia, (2023); 37(3): 550-559.
Weaver CJ, Tariman JD. Multiple Myeloma Genomics: A Systematic Review. Seminars in oncology nursing, (2017); 33(3): 237-253.
Sturm G, Finotello F, Petitprez F, Zhang JD, Baumbach J, et al. Comprehensive evaluation of transcriptome-based cell-type quantification methods for immuno-oncology. Bioinformatics, (2019); 35(14): i436-i445.
Ren X, Kuan PF. RNAAgeCalc: A multi-tissue transcriptional age calculator. PLoS One, (2020); 15(8): e0237006.
Becht E, Giraldo NA, Lacroix L, Buttard B, Elarouci N, et al. Erratum to: Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome biology, (2016); 17(1): 249.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome biology, (2014); 15(12): 550.
Kevin Blighe SR, Myles Lewis (2018) EnhancedVolcano: Publication-ready volcano plots with enhanced colouring and labeling. https://github.com/kevinblighe/EnhancedVolcano.
Garcia-Moreno A, Lopez-Dominguez R, Villatoro-Garcia JA, Ramirez-Mena A, Aparicio-Puerta E, et al. Functional Enrichment Analysis of Regulatory Elements. Biomedicines, (2022); 10(3).
Wang J, Hu Y, Hamidi H, Dos Santos C, Zhang J, et al. Immune microenvironment characteristics in multiple myeloma progression from transcriptome profiling. Front Oncol, (2022); 12948548.
Xu L, Yu W, Xiao H, Lin K. BIRC5 is a prognostic biomarker associated with tumor immune cell infiltration. Scientific reports, (2021); 11(1): 390.
Hong TM, Chen YL, Wu YY, Yuan A, Chao YC, et al. Targeting neuropilin 1 as an antitumor strategy in lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, (2007); 13(16): 4759-4768.
Chida S, Okayama H, Noda M, Saito K, Nakajima T, et al. Stromal VCAN expression as a potential prognostic biomarker for disease recurrence in stage II-III colon cancer. Carcinogenesis, (2016); 37(9): 878-887.
Wang Y, Li W, Jin X, Jiang X, Guo S, et al. Identification of prognostic immune-related gene signature associated with tumor microenvironment of colorectal cancer. BMC Cancer, (2021); 21(1): 905.
Misawa K, Kanazawa T, Imai A, Endo S, Mochizuki D, et al. Prognostic value of type XXII and XXIV collagen mRNA expression in head and neck cancer patients. Molecular and clinical oncology, (2014); 2(2): 285-291.
Deng M, Aberle MR, van Bijnen A, van der Kroft G, Lenaerts K, et al. Lipocalin-2 and neutrophil activation in pancreatic cancer cachexia. Frontiers in immunology, (2023); 14: 1159411.
Rosales C. Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types? Frontiers in physiology, (2018); 9: 113.
Parrinello N, Romano A, Conticello C, Cavalli M, La Fauci A, et al. Neutrophils Of Multiple Myeloma Are Dysfunctional and Immunosuppressive. Blood, (2013); 122(21): 3138-3138.
Romano A, Parrinello NL, Simeon V, Puglisi F, La Cava P, et al. High-density neutrophils in MGUS and multiple myeloma are dysfunctional and immune-suppressive due to increased STAT3 downstream signaling. Scientific reports, (2020); 10(1): 1983.
Maimela NR, Liu S, Zhang Y. Fates of CD8+ T cells in Tumor Microenvironment. Computational and structural biotechnology journal, (2019); 17: 1-13.
Cox AD, Der CJ. Ras history: The saga continues. Small GTPases, (2010); 1(1): 2-27.
Corre J, Cleynen A, Robiou du Pont S, Buisson L, Bolli N, et al. Multiple myeloma clonal evolution in homogeneously treated patients. Leukemia, (2018); 32(12): 2636-2647.
Hu Y, Chen W, Wang J. Progress in the identification of gene mutations involved in multiple myeloma. OncoTargets and therapy, (2019); 12: 4075-4080.
Sacco A, Federico C, Todoerti K, Ziccheddu B, Palermo V, et al. Specific targeting of the KRAS mutational landscape in myeloma as a tool to unveil the elicited antitumor activity. Blood, (2021); 138(18): 1705-1720.
Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: Mission possible? Nature reviews. Drug discovery, (2014); 13(11): 828-851.
Hobbs GA, Baker NM, Miermont AM, Thurman RD, Pierobon M, et al. Atypical KRAS(G12R) Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer. Cancer Discovery, (2020); 10(1): 104-123.
Ragusa D, Tosi S, Sisu C. Pan-Cancer Analysis Identifies MNX1 and Associated Antisense Transcripts as Biomarkers for Cancer. Cells, (2022); 11(22): 3577.
Nilsson T, Waraky A, Ostlund A, Li S, Staffas A, et al. An induced pluripotent stem cell t(7;12)(q36;p13) acute myeloid leukemia model shows high expression of MNX1 and a block in differentiation of the erythroid and megakaryocytic lineages. International journal of cancer, (2022); 151(5): 770-782.
Yang X, Pan Q, Lu Y, Jiang X, Zhang S, et al. MNX1 promotes cell proliferation and activates Wnt/beta-catenin signaling in colorectal cancer. Cell biology international, (2019); 43(4): 402-408.
de Bock CE, Ardjmand A, Molloy TJ, Bone SM, Johnstone D, et al. The Fat1 cadherin is overexpressed and an independent prognostic factor for survival in paired diagnosis-relapse samples of precursor B-cell acute lymphoblastic leukemia. Leukemia, (2012); 26(5): 918-926.
Chen ZG, Saba NF, Teng Y. The diverse functions of FAT1 in cancer progression: good, bad, or ugly? Journal of Experimental and Clinical Cancer Research, (2022); 41(1): 248.
Liebig S, Neumann M, Silva P, Ortiz-Tanchez J, Schulze V, et al. FAT1 expression in T-cell acute lymphoblastic leukemia (T-ALL) modulates proliferation and WNT signaling. Scientific reports, (2023); 13(1): 972.
Adamo P, Ladomery MR. The oncogene ERG: a key factor in prostate cancer. Oncogene, (2016); 35(4): 403-414.
Khosh Kish E, Choudhry M, Gamallat Y, Buharideen SM, D D, et al. The Expression of Proto-Oncogene ETS-Related Gene (ERG) Plays a Central Role in the Oncogenic Mechanism Involved in the Development and Progression of Prostate Cancer. International journal of molecular sciences, (2022); 23(9): 4772.
Zhou W, Su Y, Zhang Y, Han B, Liu H, et al. Endothelial Cells Promote Docetaxel Resistance of Prostate Cancer Cells by Inducing ERG Expression and Activating Akt/mTOR Signaling Pathway. Frontiers in oncology, (2020); 10: 584505.
Paduano F, Gaudio E, Mensah AA, Pinton S, Bertoni F, et al. T-Cell Leukemia/Lymphoma 1 (TCL1): An Oncogene Regulating Multiple Signaling Pathways. Frontiers in oncology, (2018); 8: 317.
Stachelscheid J, Jiang Q, Aszyk C, Warner K, Bley N, et al. The proto-oncogene TCL1A deregulates cell cycle and genomic stability in CLL. Blood, (2023); 141(12): 1425-1441.
Li H, Yan X, Liu L, Huang L, Yin M, et al. T-cell leukemia/lymphoma-1A predicts the clinical outcome for patients with stage II/III colorectal cancer. Biomed Pharmacother, (2017); 88: 924-930.
Shi Y, Zhao Y, Zhang Y, AiErken N, Shao N, et al. AFF3 upregulation mediates tamoxifen resistance in breast cancers. Journal of experimental & clinical cancer research, (2018); 37(1): 254.
xi chen QY, Xiang Qin, Jing Liu, Yan Zeng, Sili Long, Wenjun Liu. High expression of AFFs is related to prognosis of acute myeloid leukemia. PREPRINT (Version 1) available at Research Square (2021); [https://doi.org/10.21203/rs.3.rs-927123/v1]
Zeng Y, Zhang X, Li F, Wang Y, Wei M. AFF3 is a novel prognostic biomarker and a potential target for immunotherapy in gastric cancer. Journal of Clinical Laboratory Analysis, (2022); 36(6): e24437.
Lefevre L, Omeiri H, Drougat L, Hantel C, Giraud M, et al. Combined transcriptome studies identify AFF3 as a mediator of the oncogenic effects of beta-catenin in adrenocortical carcinoma. Oncogenesis, (2015); 4(7): e161.
Li C, Vides A, Kim D, Xue JY, Zhao Y, et al. The G protein signaling regulator RGS3 enhances the GTPase activity of KRAS. Science, (2021); 374(6564): 197-201.
Shi YY, Meng XT, Xu YN, Tian XJ. Role of FOXO protein's abnormal activation through PI3K/AKT pathway in platinum resistance of ovarian cancer. The journal of obstetrics and gynaecology research, (2021); 47(6): 1946-1957.
Ramakrishnan V, Kumar S. PI3K/AKT/mTOR pathway in multiple myeloma: from basic biology to clinical promise. Leuk Lymphoma, (2018); 59(11): 2524-2534.
Wang L, Lin N, Li Y. The PI3K/AKT signaling pathway regulates ABCG2 expression and confers resistance to chemotherapy in human multiple myeloma. Oncology Reports, (2019); 41(3): 1678-1690.
van Andel H, Kocemba KA, Spaargaren M, Pals ST. Aberrant Wnt signaling in multiple myeloma: molecular mechanisms and targeting options. Leukemia, (2019); 33(5): 1063-1075.
DOI: http://dx.doi.org/10.62940/als.v11i2.1900
Refbacks
- There are currently no refbacks.