Bioinformatics analyses of differentially expressed genes associated with bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma

Abstract

Jingnan Sun,1 Xue Wen,1 Fengyan Jin,1 Yuying Li,1 Jifan Hu,2 Yunpeng Sun31Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin, People’s Republic of China; 2Stanford University Medical School, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; 3Cardiovascular Surgery Department, First Affiliated Hospital, Jilin University, Changchun, Jilin, People’s Republic of ChinaPurpose: This study aimed to explore the molecular mechanisms associated with bisphosphonate (BP)-related osteonecrosis of the jaw (ONJ) in patients with multiple myeloma (MM).Methods: The gene expression profile GSE7116 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) from eleven patients with ONJ resulting from MM treated with BPs (ONJBPs) and ten MM patients without ONJ treated with BPs (MMBPs) were analyzed. Gene ontology (GO) and pathway enrichment analyses of DEGs were performed, followed by functional annotation and protein–protein interaction network construction. Finally, sub-network modules were constructed and analyzed.Results: A total of 166 up- and 473 down-regulated DEGs were identified. The up-regulated DEGs were enriched in pathways related to cancer, and the down-regulated DEGs were enriched in pathways related to the immune system. Moreover, the GO terms enriched by the up-regulated DEGs were associated with misfolded proteins, and the down-regulated DEGs were associated with immune responses. After functional annotation, 16 transcription factors were identified, including X-box binding protein 1 (XBP1). In protein–protein interaction network analysis, tumor necrosis factor (TNF) and interleukin 1, beta (IL1B) had higher connectivity degrees. Among the constructed sub-network modules, module 1 was the best one, and DEAD (Asp-Glu-Ala-Asp) box helicase 5 (DDX5) was a hub gene. The DEGs in module 1 were mainly enriched in GO terms related to RNA splicing.Conclusion: DEGs of ONJ were mainly enriched in pathways related to the immune system and RNA splicing. DEGs such as TNF, ILB1, DDX5, and XBP1 may be the potential targets of ONJ treatment.Keywords: osteonecrosis of the jaw, multiple myeloma, bisphosphonates, differentially expressed genes, functional enrichment analysis