High Serpin Family A Member 10 Expression Confers Platinum Sensitivity and Is Associated With Survival Benefit in High-Grade Serous Ovarian Cancer: Based on Quantitative Proteomic Analysis.

Wenwen Guo,Xiaoxiang Chen,Xue He,Liya Ma,Congyang Wang,Xianzhong Cheng,Yan Wang,Jing Ni

doi:10.3389/fonc.2021.761960

Abstract

This study aims to identify differentially expressed proteins related with platinum sensitivity and to find biomarkers for predicting platinum response and survival outcomes in patients with high-grade serous ovarian cancer (HGSOC). Eligible HGSOC patients were divided into platinum-sensitive and platinum-resistant groups according to platinum-free interval (PFI). Tissue protein lysates from tumor tissues were subjected to an in-solution tryptic digest followed by tandem mass tag (TMT) labeling of the resulting peptides and mass spectrometric analysis. Candidate proteins were identified using differentially expressed protein and gene set enrichment analysis (GSEA) and confirmed by immunohistochemistry (IHC), and their survival relevance was evaluated in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. The results showed that there was a significant difference in the protein expression profiling between the two patient groups. In the GSEA model, a gene set of 239 extracellular matrix (ECM)-related proteins was significantly enriched in the platinum-sensitive group [normalized enrichment score (NES) = 3.82, q < 10−5], and this finding was confirmed in TCGA ovarian cancer cohort. Interestingly, an ECM-related gene expression, serpin family A member 10 (SERPINA10), was identified to be significantly positively correlated with overall survival (OS) and progression-free survival (PFS) in TCGA ovarian cancer cohort (all p < 0.05). IHC results demonstrated that HGSOC patients with high SERPINA10 expression had longer PFI than the patients with low SERPINA10 expression (9 vs. 5 months, p = 0.038), and the SERPINA10 expression had an area under the receiver operating characteristic curve (AUC) value of 0.758 (95% CI = 0.612–0.905; p = 0.005) to discriminate the platinum-sensitive group from the platinum-resistant group. In conclusion, the results suggested that SERPINA10 could be a promising biomarker for predicting the response and survival in platinum-based chemotherapy of HGSOC.

Highlights

Ovarian cancer is the most lethal gynecologic malignancy [1], of which high-grade serous ovarian cancer (HGSOC) is the most prevalent and aggressive histologic subtype and accounts for 70%–80% of deaths [2, 3]
To explore gene signature-related platinum sensitivity of HGSOC tumors, the proteomic analysis was performed in cohort 1 subjects
To determine whether samples clustered based on the platinum sensitivity, we performed a principal component analysis (PCA) on the quantitative proteins of proteomics across all samples

Summary

Introduction

Ovarian cancer is the most lethal gynecologic malignancy [1], of which high-grade serous ovarian cancer (HGSOC) is the most prevalent and aggressive histologic subtype and accounts for 70%–80% of deaths [2, 3]. The major obstacle to clinical application of platinum-based chemotherapy is the resistance by tumor cells, which can result in the failure of therapy, relapse, and even death. Response to platinum-containing anticancer drugs is an essential prognostic determinant for survival in HGSOC patients. It is necessary to explore relevant biomarkers in predicting the response and targets in overcoming resistance to the platinum-containing drugs in the treatment of ovarian cancer. In order to explore the molecular basis of platinum resistance and further determine a potential biomarker for platinum sensitivity prediction, we analyzed the differentially expressed proteins of tumor tissues from platinum-sensitive and platinum-resistant HGSOC patient groups by proteomic analysis and investigated their possible clinical relevance and performance for prediction of platinum sensitivity in ovarian cancer treatment. The results suggested that a set of extracellular matrix (ECM)-related proteins might be the molecular basis of a platinum-sensitive phenotype of HGSOC and identified a promising protein marker involved in the ECM that could predict platinum sensitivity of HGSOC patients

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