Identification of a novel cuproptosis‐related gene signature for multiple myeloma diagnosis

Abstract

BackgroundMultiple myeloma (MM) ranks second among the most prevalent hematological malignancies. Recent studies have unearthed the promise of cuproptosis as a novel therapeutic intervention for cancer. However, no research has unveiled the particular roles of cuproptosis‐related genes (CRGs) in the prediction of MM diagnosis.MethodsMicroarray data and clinical characteristics of MM patients were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed gene analysis, least absolute shrinkage and selection operator (LASSO) and support vector machine‐recursive feature elimination (SVM‐RFE) algorithms were applied to identify potential signature genes for MM diagnosis. Predictive performance was further assessed by receiver operating characteristic (ROC) curves, nomogram analysis, and external data sets. Functional enrichment analysis was performed to elucidate the involved mechanisms. Finally, the expression of the identified genes was validated by quantitative real‐time polymerase chain reaction (qRT‐PCR) in MM cell samples.ResultsThe optimal gene signature was identified using LASSO and SVM‐RFE algorithms based on the differentially expressed CRGs: ATP7A, FDX1, PDHA1, PDHB, MTF1, CDKN2A, and DLST. Our gene signature‐based nomogram revealed a high degree of accuracy in predicting MM diagnosis. ROC curves showed the signature had dependable predictive ability across all data sets, with area under the curve values exceeding 0.80. Additionally, functional enrichment analysis suggested significant associations between the signature genes and immune‐related pathways. The expression of the genes was validated in MM cells, indicating the robustness of these findings.ConclusionWe discovered and validated a novel CRG signature with strong predictive capability for diagnosing MM, potentially implicated in MM pathogenesis and progression through immune‐related pathways.

Transcriptional Remodeling of the Stromal and Endothelial Microenvironment in MGUS to Multiple Myeloma Progression

“…Metallothioneins (Mts) are metal-binding proteins that play a role in several processes, including metal homeostasis, detoxification, and cell proliferation 16 . Although their connection to myeloma is less well characterized, several studies have demonstrated that metallothioneins play an essential role in tumor angiogenesis 17 . These results suggest that the upregulation of Mt1 and Mt2 in EC from MGUS may be involved in neovessel formation and may represent a “pre-vascular phase” in the progression to MM.…”

“…Examining the molecular mechanisms governing myeloma progression within non-IFN EC identified transcriptional and regulatory changes during MGUS related to protein folding and ion homeostasis. The upregulation of Slpi, Mt1, Mt2, and Hspa5, known for their roles in tumor angiogenesis and pro-survival signaling 49,50 may serve as promising early indicators of myeloma development in EC. Comparison of MGUS and MM EC reveals dynamic changes associated with disease progression, including angiogenesis, migration, and lipid metabolism, reflecting the vascular phenotype and metabolic alterations characteristic of MM EC.…”

“…The examination of the molecular mechanisms governing myeloma progression within non-IFN EC identified transcriptional and regulatory changes during MGUS with the upregulation of genes related to protein folding and metal ion homeostasis, such as heat shock proteins and metallothioneins. The upregulation of genes such as Slpi, Mt1, Mt2 , and Hspa5 , known for their roles in tumor angiogenesis and pro-survival signaling 17,53 may serve as promising early indicators of myeloma development in EC. Remarkably, our analysis unveils unexpected upregulation of genes like Cd74, Tmem176a , and Nme2 in MGUS EC, indicating their potential involvement in MM pathogenesis, although their precise roles require further elucidation.…”