Wei Lu

Integrative Analysis of Novel Ferroptosis‐Related Genes Signatures as Prognostic Biomarkers in Ovarian Cancer

ABSTRACTBackgroundFerroptosis, an iron‐dependent form of cell death, has been implicated in the pathogenesis of several types of cancer. Nevertheless, the exact correlation between ferroptosis‐related gene mutations and their influence on ovarian cancer (OV) diagnosis and treatment strategies remains to be fully elucidated. It is crucial to identify the ferroptosis‐related gene signature in OV and elucidate the impact of these mutations and their expression on the diagnosis and treatment of OV.MethodsIn this study, we collected data from the TCGA and GEO databases. We utilized various tools and packages for data analysis, including the cBio Cancer Genomics Portal, Tumor Immune Estimation Resource (TIMER), GSVA package, and WGCNA R packages.ResultsOur results showed that ferroptosis subtypes 1 (FS1) and 2 (FS2) exhibited different levels of expression and tumor mutation burden (TMB). FS2 had a higher TMB level and survival rate compared to FS1. Furthermore, our analysis identified three ferroptosis‐related genes, including IFNG, KEAP1, and PHKG2, as key biomarkers in prognosis prediction and potential targets for OV cancer therapy. The elevated expression levels of IFNG, KEAP1, and PHKG2 were found to be correlated with a good prognosis. These three genes showed a positive correlation with TMB in OV. We also observed that high TMB was more robustly associated with immune response‐related gene expression, including CD28, CD40L, and type I IFN family members. Moreover, high TMB was associated with increased T cell infiltration and exhibited a distinct gene signature, which highlights the potential of IFNG, KEAP1, and PHKG2 as predictive markers for T cell infiltration and the tumor microenvironment status in OV. A significant correlation exists between the expression levels of KEAP1 and PHKG2 and TMB in OV cell lines.ConclusionIn conclusion, our study identified KEAP1, IFNG, and PHKG2 as potential prognostic biomarkers and therapeutic targets in OV. Their expression and mutation burden were correlated with a good prognosis. The association between ferroptosis subtypes, TMB, and survival rates further supports the relevance of these biomarkers. Additionally, the positive correlation between KEAP1, IFNG, and PHKG2 with TMB and immune response‐related gene expression highlights their potential as predictive markers for immunotherapy efficacy in OV. The observed association of high TMB with increased T cell infiltration and distinct gene signature further emphasizes its role as a potential biomarker for immune response. Further research is warranted to validate these findings and explore their clinical implications in OV treatment.

Surgical and Blood-Based Minimal Residual Disease in Patients with Ovarian Cancer after First-line Therapy: Clinical Outcomes and Translational Opportunities

Abstract Purpose: Minimal residual disease (MRD) after first-line treatment of advanced-stage ovarian cancer remains a long-standing barrier to cure. We investigated the prognostic and translational value of MRD detection by second-look laparoscopy (SLL) and ctDNA at the completion of first-line therapy. Experimental Design: Patients with high-grade epithelial ovarian cancer who had a complete clinical response to first-line therapy and underwent SLL and plasma collection for ctDNA were included. Progression-free survival (PFS) and overall survival (OS) were estimated based on MRD and clinicopathologic status. Spatial transcriptomics (GeoMx and Visium) and proteomics (CODEX) profiling were performed on serial samples from select patients. Results: Forty of 95 (42.1%) patients had surgically detected MRD, which was associated with worse PFS (median PFS 7.4 vs. 23.8 months; P < 0.001) and OS (median OS 33.9 vs. not reached; P < 0.001). SLL positivity was an independent negative prognostic factor for OS (HR, 4.40; 95% confidence interval, 1.37–14.21; P = 0.013) in multivariable analysis. Among 44 patients who underwent SLL and had ctDNA testing, 34% (15/44) were ctDNA-positive, which was associated with worse PFS (6.4 vs. 28.1 months; P < 0.001) and OS (32.4 months vs. not reached; P = 0.008). We demonstrated the feasibility of spatial multiomics in studying MRD and their ability to provide hypothesis-generating observations, implicating the upregulation of the hypoxia signaling pathway, expression of multiple druggable targets (CDK6, GLS, MSLN, ERBB2), and immune exclusion in MRD lesions. Conclusions: Approximately half of patients in clinical remission after first-line therapy have assessable MRD, which can inform prognosis, therapeutic target discovery, and clinical trials.