Abstract
Initial identification of biomarkers predicting the exact prognosis of high-grade serous ovarian carcinoma (HGSOC) is important in precision cancer medicine. This study aimed to investigate prognostic biomarkers of HGSOC through proteomic analysis. We conducted label-free liquid chromatography-mass spectrometry using chemotherapy-naïve, fresh-frozen primary HGSOC specimens, and compared the results between a favorable prognosis group (progression-free survival (PFS) ≥ 18 months, n = 6) and a poor prognosis group (PFS < 18 months, n = 6). Among 658 differentially expressed proteins, 288 proteins were upregulated in the favorable prognosis group and 370 proteins were upregulated in the poor prognosis group. Using hierarchical clustering, we selected α1-antitrypsin (AAT), nuclear factor-κB (NFKB), phosphomevalonate kinase (PMVK), vascular adhesion protein 1 (VAP1), fatty acid-binding protein 4 (FABP4), platelet factor 4 (PF4), apolipoprotein A1 (APOA1), and α1-acid glycoprotein (AGP) for further validation via immunohistochemical (IHC) staining in an independent set of chemotherapy-naïve primary HGSOC samples (n = 107). Survival analyses revealed that high expression of AAT, NFKB, and PMVK were independent biomarkers for favorable PFS. Conversely, high expression of VAP1, FABP4, and PF4 were identified as independent biomarkers for poor PFS. Furthermore, we constructed models predicting the 18-month PFS by combining clinical variables and IHC results. Through leave-one-out cross-validation, the optimal model was based on initial serum CA-125, germline BRCA1/2 mutations, residual tumors after surgery, International Federation of Gynecology and Obstetrics (FIGO) stage, and expression levels of the six proteins. The present results elucidate the proteomic landscape of HGSOC and six protein biomarkers to predict the prognosis of HGSOC.
Highlights
Ovarian cancer, one of the most fatal gynecologic malignancies, is a global burden with 295,414 new cases and 184,799 deaths estimated each year [1]
To identity prognostic biomarkers for high-grade serous ovarian carcinoma (HGSOC), we performed Mass spectrometry (MS)-based label-free quantification using chemotherapy-naïve, fresh-frozen cancer tissues resected from the primary ovarian mass intraoperatively during the debulking surgery (n = 12); the good and poor prognosis groups contained six patients per group (Figure 1A)
On multivariate analyses adjusting patient age at diagnosis, initial serum cancer antigen 125 (CA-125) level, Federation of Gynecology and Obstetrics (FIGO) stage, residual tumor after surgery, and germline BRCA1/2 mutational status, high expression of AAT, nuclear factor-κB (NFKB), and phosphomevalonate kinase (PMVK) were identified as independent favorable prognostic biomarkers for progression-free survival (PFS) (AAT (adjusted hazard ratio, 0.398; 95% confidence interval (CI), 0.207–0.768; p = 0.006), NFKB, and PMVK)
Summary
One of the most fatal gynecologic malignancies, is a global burden with 295,414 new cases and 184,799 deaths estimated each year [1]. Mass spectrometry (MS)-based proteomics has been widely used to characterize molecular components and underlying mechanisms associated with various malignancies such as colorectal [7], breast [8], lung [9], and ovarian cancers [10,11,12]. This emerging technology is used for high-throughput analysis for simultaneous quantification of numerous proteins and discovery of prognostic biomarkers in individual samples. These biomarkers need to be subjected to specific validation studies before being clinically applied
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