Exploration of Potential Diagnostic Value of Protein Content in Serum Small Extracellular Vesicles for Early-Stage Epithelial Ovarian Carcinoma.

Huaying Wang,Zhengchen Guo,Xiaoya Xu,Pu Li,Boer Shan,Yingjie Zhu,Yuanjing Hu,Wei Zhang,Zhanjie Liu,Yanan Zhang,Xiujie Sheng,Qian Chen,Yuezong Bai,Xiaoyang Deng,Dadong Zhang

doi:10.3389/fonc.2021.707658

Abstract

Epithelial ovarian carcinoma (EOC) is one of the most common gynecologic malignancies with a high mortality rate. Serum biomarkers and imaging approaches are insufficient in identifying EOC patients at an early stage. This study is to set up a combination of proteins from serum small extracellular vesicles (sEVs) for the diagnosis of early-stage EOC and to determine its performance. A biomarker for early-stage ovarian cancer (BESOC) cohort was used as a Chinese multi-center population-based biomarker study and registered as a Chinese Clinical Trial ChiCTR2000040136. The sEV protein levels of CA125, HE4, and C5a were measured in 299 subjects. Logistic regression was exploited to calculate the odds ratio and to create the sEV protein model for the predicted probability and subsequently receiver-operating characteristic (ROC) analysis. The combined sEV marker panel of CA125, HE4, and C5a as a sEV model obtained an area under curve (AUC) of 0.912, which was greater than the serum model (0.809), by ROC analysis to identify EOC patients from the whole cohort. With the cutoff of 0.370, the sensitivity and specificity of the sEV model were 0.80 and 0.89, which were much better performance than the serum markers (sensitivity: 0.55~0.66; specificity: 0.59~0.68) and the risk of ovarian malignancy algorithm (ROMA) index approved by the U.S. Food and Drug Administration (sensitivity: 0.65; specificity: 0.61), to identify EOC patients from patients with benign ovarian diseases or other controls. The sEV levels of CA125 significantly differed among early-stage and late-stage EOC (p < 0.001). Moreover, the AUC of ROC to identify early-stage EOC patients was 0.888. Further investigation revealed that the sEV levels of these 3 proteins significantly decreased after cytoreductive surgery (CA125, p = 0.008; HE4, p = 0.025; C5a, p = 0.044). In summary, our study showed that CA125, HE4, and C5a levels in serum sEVs can identify EOC patients at the early stage, elucidating the possibility of using a sEV model for the diagnosis of early-stage EOC.

Highlights

Ovarian cancer is the leading gynecologic malignancy and the most common cause of gynecologic cancer death [1]
electron microscopy (EM), western blotting (WB), and nanoparticle tracking analysis (NTA) results to qualify the minimum information for studies of extracellular vesicles 2018 (MISEV2018) [26] are shown (Figure S2)
This novel serum sEV model has been compared with the current serum protein marker HE4 and CA125, as well as risk of ovarian malignancy algorithm (ROMA), which was approved by the U.S Food and Drug Administration (FDA) (510(k) Number: k103358)

Summary

Introduction

Ovarian cancer is the leading gynecologic malignancy and the most common cause of gynecologic cancer death [1]. 95% of primary ovarian malignancies originate from epithelial cells [2, 3]. The prognosis of early-stage patients is satisfactory (the five-year survival rates of International Federation of Gynecology and Obstetrics (FIGO) stage I and II patients are 81.3% and 66.9%, respectively, and the five-year survival rates of FIGO stage III and IV patients are only 41.3% and 31.3%, respectively) [4]. More than 60% of patients with ovarian cancer are diagnosed at advanced stages. The high mortality rate of epithelial ovarian carcinoma (EOC) can be attributed to the fact that the majority of patients are diagnosed with advanced disease [5]. An approach to identify EOC at an early, localized, and curable stage can significantly reduce mortality rate

Methods

Results

Discussion

Conclusion