Comprehensive Analyses Identify APOBEC3A as a Genomic Instability-Associated Immune Prognostic Biomarker in Ovarian Cancer

Abstract

Ovarian cancer (OC) is one of the most malignant tumors whose mortality rate ranks first in gynecological tumors. Although immunotherapy sheds new light on clinical treatments, the low response still restricts its clinical use because of the unique characteristics of OC such as immunosuppressive microenvironment and unstable genomes. Further exploration on determining an efficient biomarker to predict the immunotherapy response of OC patients is of vital importance. In this study, integrative analyses were performed systematically using transcriptome profiles and somatic mutation data from The Cancer Genome Atlas (TCGA) based on the immune microenvironment and genomic instability of OC patients. Firstly, intersection analysis was conducted to identify immune-related differentially expressed genes (DEGs) and genomic instability-related DEGs. Secondly, Apolipoprotein B MRNA Editing Enzyme Catalytic Subunit 3A (APOBEC3A) was recognized as a protective factor for OC, which was also verified through basic experiments such as quantitative reverse transcription PCR (RT-qPCR), immunohistochemistry (IHC), Cell Counting Kit-8 (CCK-8), and transwell assays. Thirdly, the correlation analyses of APOBEC3A expression with tumor-infiltrating immune cells (TICs), inhibitory checkpoint molecules (ICPs), Immunophenoscores (IPS), and response to anti-PD-L1 immunotherapy were further applied along with single-sample GSEA (ssGSEA), demonstrating APOBEC3A as a promising biomarker to forecast the immunotherapy response of OC patients. Last, the relationship between APOBEC3A expression with tumor mutation burden (TMB), DNA damage response (DDR) genes, and m6A-related regulators was also analyzed along with the experimental verification of immunofluorescence (IF) and RT-qPCR, comprehensively confirming the intimate association of APOBEC3A with genomic instability in OC. In conclusion, APOBEC3A was identified as a protective signature and a promising prognostic biomarker for forecasting the survival and immunotherapy effect of OC patients, which might accelerate the clinical application and improve immunotherapy effect.

Development and validation of a genomic instability-related lncRNA prognostic model for hepatocellular carcinoma

“…It has also been reported that the genetically unstable type of breast cancer has a higher risk of significantly shorter recurrence-free survival and metastasis-free survival than other types ( Duijf et al, 2019 ). Consistent with previous reports, genomic instability is also associated with a poor prognosis in colorectal cancer, ovarian cancer and other tumors ( Xu et al, 2021 ; Lakbir et al, 2022 ). However, studies have shown that extreme genetic instability is correlated with a better prognosis ( Andor et al, 2017 ).…”

Protein Panel of Serum-Derived Small Extracellular Vesicles for the Screening and Diagnosis of Epithelial Ovarian Cancer

“…APOA4 is not only a lipid-binding protein, but also has a role in the immune response [ 39 , 40 ]. Our model not only reflects the key role of CA125 for diagnosing ovarian cancer, but also suggests that the occurrence and development of ovarian cancer may be accompanied by the remodeling of cellular lipid metabolism and the complex interaction between the tumor and their hosts’ immune system [ 41 , 42 , 43 , 44 ]. These findings suggest that these proteins within sEVs found in our study can serve as diagnostic markers for ovarian cancer and provide new perspectives for therapeutic research on ovarian cancer.…”

Elafin is related to immune infiltration and could predict the poor prognosis in ovarian cancer

“…The Spearman correlation analysis of data from the TISIDB web showed that the common ICPs ( 40 ), including PDL1 (CD274), CTLA4, ICOS, LAG3, PDCD1, CD48, CD86, and TIGIT, were all significantly associated with elafin expression ( P < 0.05; Figures 7A–I ).…”