Discover. Oncology最新文献

Background: Resistance to the proteasome inhibitor bortezomib is a major obstacle to the treatment of multiple myeloma (MM) and a major cause of relapse and death. Investigating the role of bortezomib resistance genes in MM is crucial. This study aimed to evaluate the potential of bortezomib resistance-related genes (BRGs) as prognostic biomarkers in MM.

Methods:  The transcriptome data of bortezomib resistant myeloma cell lines, as well as the gene expression and clinical data of patients were downloaded from the Gene Expression Omnibus (GEO) database. Univariate Cox and least absolute shrinkage and selection operator (LASSO) Cox regression models were employed to screen variables and construct a multigene prognostic signature based on BRGs. Single-sample gene set enrichment analysis (ssGSEA) was performed to quantify the relative infiltration levels of immune cells. The pRRophetic algorithm was utilized to assess and infer the sensitivity of anti-MM chemotherapeutics.

Results: We identified 129 differentially expressed BRGs, with 25 associated with MM prognosis. Using the LASSO Cox regression model, we identified five key genes (IFI16, ARID5B, LTBP1, PNOC, CRIP1) and developed a bortezomib resistance model for risk stratification and prognosis prediction. Multivariate Cox regression analysis revealed that the risk score was an independent prognostic factor for overall survival (OS). Based on pRRophetic results, high-risk patients may be more sensitive to other chemotherapeutic agents, such as doxorubicin and etoposide. Additionally, we constructed a nomogram incorporating patient age, LDH, International Staging System (ISS), and BRGs, which demonstrated robust prognostic prediction capabilities. The receiver operating characteristic (ROC) values for 1-, 3-, and 5-years survival rates were 0.730, 0.734, and 0.775, respectively. We also validated the expression patterns of the five key genes in MM. IFI16 and CRIP1 expression levels were upregulated in relapsed patients, whereas ARID5B expression was decreased. PNOC and LTBP1 showed no significant differences. Notably, lower ARID5B expression was associated with poorer OS in patients.

Conclusions: The BRGs signature is a reliable biomarker for predicting the prognosis of MM and helps optimize clinical decision-making for treatment, and identifies key gene ARID5B downregulation as an adverse prognostic factor in multiple myeloma.

Background: Emerging evidence highlights the overexpression of Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) in multiple malignancies. However, its pan-cancer prognostic significance, tumor immune microenvironment (TIME) interactions, and therapeutic implications remain underexplored.

Methods: Multi-omics data were integrated from UCSC Xena, GTEx, UALCAN, and published cohorts. PCMT1 expression patterns were systematically analyzed across 33 cancer types. Associations between PCMT1 and clinical outcomes, immune infiltration, immune checkpoint genes (ICGs), tumor mutation burden (TMB), microsatellite instability (MSI), and drug sensitivity were evaluated using bioinformatics pipelines.

Results: Our pan-cancer analysis revealed differential expression patterns of PCMT1 across various malignancies, with significant upregulation in 20 cancer types and downregulation in 3 cancer types. Notably, PCMT1 overexpression was predominantly observed in epithelial-origin tumors, such as ACC (adrenocortical carcinoma), BRCA (breast invasive carcinoma), COAD (colon adenocarcinoma), and LUAD (lung adenocarcinoma). Survival analysis demonstrated that elevated PCMT1 expression was significantly correlated with unfavorable prognosis in multiple epithelial tumors, particularly in BRCA, esophageal carcinoma (ESCA), head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LIHC), and mesothelioma (MESO). Furthermore, comprehensive analysis identified significant associations between PCMT1 expression and various tumor microenvironment features, including immune scores, six distinct immune cell types, four immunosuppressive cell populations, cancer-associated fibroblasts (CAFs)-related markers, and immunosuppressive factors. PCMT1 expression also showed significant correlations with tumor mutation burden (TMB), microsatellite instability (MSI), DNA stemness score (DNAss), and RNA stemness score (RNAss). Particularly noteworthy was the strong positive correlation between PCMT1 expression and CAFs infiltration, along with their associated factors. These findings were further validated in independent immunotherapy cohorts, where PCMT1 consistently demonstrated immunosuppressive characteristics.

Conclusion: Multi-omics analysis suggests that PCMT1 may serve as a potential prognostic biomarker and a novel immunotherapy target for pan-cancer.

Pancreatic cancer is a highly aggressive malignancy with serious threat to human health and survival. Cavin1, a caveolin-associated protein, has recently been identified as a differentially expressed gene linked to lipid droplet formation, suggesting its potential involvement in pancreatic cancer biology. However, the significance and underlying mechanisms of Cavin1 in the progression of pancreatic cancer remain poorly understood. In this present study, we demonstrated that Cavin1 expression was significantly elevated in pancreatic cancer, its knockdown significantly inhibited cell proliferation, and its suppression enhanced apoptotic activity in pancreatic cancer cells. In addition, inhibition of Cavin1 impaired lipid metabolism, and silencing of Cavin1 activated the adenosine 5'-monophosphate-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signaling pathway. In conclusion, Cavin1 depletion was found to impair tumor cell growth by inhibiting proliferation and lipid metabolism while promoting apoptosis, supporting Cavin1 as a potential therapeutic target for pancreatic cancer management.

Background: While mutations in DNA repair gene (DDR) or TP53 alone have been linked to favorable outcomes in immunotherapy, their co-mutations may not have the same effect. The co-occurrence of DDR and TP53 mutations may actually impair DNA repair, cause more genomic instability, and worsen prognosis, indicating that they may have a context-specific effect.

Methods: Clinical characteristics and next-generation sequencing (NGS) data of non-small-cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs) were collected from cBioPortal ( www.cbioportal.org ). The incidence of DDR mutations was calculated. Kaplan-Meier analyses were performed to determine overall survival (OS) for the DDR+/TP53+ group vs. the DDR+/TP53- group using log-rank testing (p = 0.034). Univariate and multivariate Cox analyses were performed to establish prognostic value.

Results: Of the 350 patients studied, 78.6% had DDR mutations, 62% had TP53 mutations. The presence of DDR mutation status demonstrated a significant association with tumor mutational burden (TMB). Patients with DDR+/TP53+ mutations had shorter OS outcomes than DDR+/TP53-. Multivariable analysis confirmed that the presence of co-mutations was an independent predictor of poor outcome and diminished ICI efficacy.

Conclusion: While previous reports would suggest that the mutation status of DDR or TP53 leads to a benefit, our results demonstrate that upon co-mutations of DDR/TP53, mutant patients have inferior outcomes in NSCLC for immunotherapy treatments. This signifies that co-mutation status is an important consideration in biomarker-driven treatment strategies.