Plasma Protein Biomarkers Associated with Higher Ovarian Cancer Risk in BRCA1/2 Carriers
by
, , ,
Hee-Sung Ahn
1
,
Jung Yoon Ho
2,3, 
Jiyoung Yu
1,
Jeonghun Yeom
4,
Sanha Lee
2,
Soo Young Hur
2,3,
Yuyeon Jung
2,3,
Kyunggon Kim
1,5,6,7,* and
Youn Jin Choi
2,3,* 1
Asan Medical Center, Asan Institute for Life Sciences, Seoul 05505, Korea
2
Department of Obstetrics and Gynecology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
3
Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
4
Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea
5
Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, Korea
6
Convergence Medicine Research Center, Asan Medical Center, Clinical Proteomics Core Laboratory, Seoul 05505, Korea
7
Asan Medical Center, Bio-Medical Institute of Technology, Seoul 05505, Korea
*
Authors to whom correspondence should be addressed.
Cancers 2021, 13(10), 2300; https://doi.org/10.3390/cancers13102300
Submission received: 26 February 2021
/
Revised: 3 May 2021
/
Accepted: 8 May 2021
/
Published: 11 May 2021
(This article belongs to the Special Issue Cause, Screening and Diagnosis in Ovarian Cancer)
Simple Summary
Most hereditary ovarian cancer is associated with BRCA1/2 variants, and risk-reducing salpingo-oophorectomy during the follow-up monitoring of ovarian cancer development in heathy women with the BRCA1/2 variant reduces ovarian cancer incidence. The aim of this study was to identify plasma protein biomarkers that can indicate an increased risk of developing ovarian cancer using a proteomic approach based on a population of genetic variants. Two identified biomarkers among differentially expressed proteins, SPARC and THBS1, had lower plasma concentrations in healthy BRCA1/2 variant carriers than in ovarian cancer patients with the BRCA1/2 variant; concentration of two proteins increased at the onset of ovarian cancer. These protein markers from non-invasive liquid biopsy sampling could be used to help women with the BRCA1/2 variant determine whether to undergo an oophorectomy that could potentially affect the quality of life.
Abstract
Ovarian cancer (OC) is the most lethal gynecologic malignancy and in-time diagnosis is limited because of the absence of effective biomarkers. Germline BRCA1/2 genetic alterations are risk factors for hereditary OC; risk-reducing salpingo-oophorectomy (RRSO) is pursued for disease prevention. However, not all healthy carriers develop the disease. Therefore, identifying predictive markers in the BRCA1/2 carrier population could help improve the identification of candidates for preventive RRSO. In this study, plasma samples from 20 OC patients (10 patients with BRCA1/2 wild type (wt) and 10 with the BRCA1/2 variant (var)) and 20 normal subjects (10 subjects with BRCA1/2wt and 10 with BRCA1/2var) were analyzed for potential biomarkers of hereditary OC. We applied a bottom-up proteomics approach, using nano-flow LC-MS to analyze depleted plasma proteome quantitatively, and potential plasma protein markers specific to the BRCA1/2 variant were identified from a comparative statistical analysis of the four groups. We obtained 1505 protein candidates from the 40 subjects, and SPARC and THBS1 were verified by enzyme-linked immunosorbent assay. Plasma SPARC and THBS1 concentrations in healthy BRCA1/2 carriers were found to be lower than in OC patients with BRCA1/2var. If plasma SPARC concentrations increase over 337.35 ng/mL or plasma THBS1 concentrations increase over 65.28 μg/mL in a healthy BRCA1/2 carrier, oophorectomy may be suggested.
Keywords:
liquid biopsy; ovarian cancer; BRCA1/2; plasma; proteome; biomarker; LC-MS/MS; ELISA
