Proteomics-Derived Biomarker Panel Improves Diagnostic Precision to Classify Endometrioid and High-grade Serous Ovarian Carcinoma

Abstract

Purpose: Ovarian carcinomas are a group of distinct diseases classified by histotypes. As histotype-specific treatment evolves, accurate classification will become critical for optimal precision medicine approaches. Experimental Design: To uncover differences between the two most common histotypes, high-grade serous (HGSC) and endometrioid carcinoma, we performed label-free quantitative proteomics on freshly frozen tumor tissues (HGSC, n ¼ 10; endometrioid carcinoma, n ¼ 10). Eight candidate protein biomarkers specific to endometrioid carcinoma were validated by IHC using tissue microarrays representing 361 cases of either endometrioid carcinoma or HGSC. Results: More than 500 proteins were differentially expressed (P < 0.05) between endometrioid carcinoma and HGSC tumor proteomes. A ranked set of 106 proteins was sufficient to correctly discriminate 90% of samples. IHC validated KIAA1324 as the most discriminatory novel biomarker for endometrioid carcinoma. An 8-marker panel was found to exhibit superior performance for discriminating endometrioid carcinoma from HGSC compared with the current standard of WT1 plus TP53 alone, improving the classification rate for HGSC from 90.7% to 99.2%. Endometrioid carcinoma-specific diagnostic markers such as PLCB1, KIAA1324, and SCGB2A1 were also significantly associated with favorable prognosis within endometrioid carcinoma suggesting biological heterogeneity within this histotype. Pathway analysis of proteomic data revealed differences between endometrioid carcinoma and HGSC pertaining to estrogen and interferon signalling. Conclusions: In summary, these findings support the use of multi-marker panels for the differential diagnosis of difficult cases resembling endometrioid carcinoma and HGSC.

Decreased secretoglobin family 2A member 1expression is associated with poor outcomes in endometrial cancer

“…Furthermore, this was positivity correlated with advanced pathological stage (P=0.013) and node metastasis. Limited reports have revealed the role of SCGB2A1 in gynecological cancer types (19,30,31). It has been reported that SCGB2A1 is significantly elevated in epithelial ovarian cancer tissue compared with normal ovarian tissues (32).…”

“…SCGB2A1 is highly expressed in human tears, breast and uterus tissue, and is involved in regulating androgen biosynthesis and the androgen receptor/steroid signaling pathway in prostate cancer (17). SCGB2A1 is the top differentially expressed gene in primary epithelial ovarian cancer with a 905-fold upregulation (18)(19)(20). In invasive and borderline ovarian carcinoma, presentation of SCGB2A1 expression was correlated to less aggressive behavior and a more favorable outcome (21).…”

Neutrophil extracellular trap formation correlates with improved overall survival in ovarian cancer

“…5I). NETs proteins and S100A8/CRP ratio were up-regulated in ovarian cancer patients with favorable outcome of another recent study [50] (Fig. S4A).…”

Neutrophil Extracellular Trap Formation Correlates with Favorable Overall Survival in High Grade Ovarian Cancer

“…In line, the S100A8/CRP abundance ratio was again found significantly up-regulated in the group of patients with OSD > 1000 as calculated from proteomics data of metastatic tumors isolated from HGSOC patients combining the study by Coscia et al [50] and a more recent study by Eckert et al (Figure 5G,H, n = 36) [51] Kaplan-Meier analysis confirmed that patients with an S100A8/CRP abundance ratio equal or above a cutoff value of 3.038 showed a significantly longer overall survival time compared to patients with values below this cutoff ( Figure 5I). NETs proteins and S100A8/CRP ratio were up-regulated in ovarian cancer patients with favorable outcome of another recent study [52] (Figure S4A). Thus, we calculated the ratio of the two proteins in a total of six studies ( Figure 1A, Figure 5A-G and Figure S4 ) representing all kinds of variations based on different patient cohorts and methodological details.…”