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

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

doi:10.3389/fonc.2021.707658

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

Front Oncol. 2021 Sep 15:11:707658. doi: 10.3389/fonc.2021.707658. eCollection 2021.

Authors

Pu Li¹, Yuezong Bai^{2

3}, Boer Shan⁴, Wei Zhang⁴, Zhanjie Liu², Yingjie Zhu⁵, Xiaoya Xu², Qian Chen⁵, Xiujie Sheng⁶, Xiaoyang Deng⁷, Zhengchen Guo¹, Dadong Zhang², Huaying Wang⁴, Yanan Zhang², Yuanjing Hu¹

Affiliations

¹ Department of Gynecology Oncology, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China.
² 3D Medicines Inc., Shanghai, China.
³ Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.
⁴ Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
⁵ Department of Gynecology, Yunnan Tumor Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China.
⁶ Key Laboratory for Major Obstetric Diseases of Guangdong Province, Gynecology Department of the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁷ Gynecology Department, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China.

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.

Keywords: early diagnosis; epithelial ovarian carcinoma; multi-center population-based study; protein contents; serum; small extracellular vesicle.