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Introduction: Improvements in blood-based biomarkers for distinguishing between indolent and aggressive prostate cancer are critical in enhancing the management of the disease. To address this, we have focused on the quantification of autoantibodies (AAbs) against tumor antigens present in the sera of patients. We have selected SPARC and Fetuin-A (also known as Alpha 2-HS Glycoprotein [AHSG]) for analysis as they are shown to be highly expressed at late stages of prostate cancer. The objectives of this study are: 1) To measure AAbs against SPARC and Fetuin-A in the sera of prostate cancer patients; 2) To determine whether there is a correlation between levels of SPARC and Fetuin-A AAbs in serum, disease and race status. Methods: Sera from prostate cancer patients and healthy controls were evaluated for AAbs against SPARC and Fetuin-A by using recombinant full-length proteins as substrates in an enzyme-linked immunosorbent assay (ELISA) assay. Sera from 117 Caucasian American (CA) n= and 111 African American (AA) prostate cancer patients with Gleason grades 6-10, and healthy controls (CA, n=52; AA, n=45) were analyzed in addition to sera from a biopsy cohort (n=99). The specificity of AAbs against the respective target proteins was confirmed by immunoblot analysis. Results: SPARC AAbs were detected in the sera, with significantly lower levels in both CA (p Conclusions: In this study, we established the presence of AAbs against SPARC in prostate cancer patient serum for the first time. More importantly, we observed highly significant differences between prostate cancer patient (low) and controls (high) sera, across different ethnic groups, similar to AAbs noted against Fetuin-A. These data support the further evaluation of SPARC and Fetuin-A AAbs as promising serum biomarkers for prostate cancer. Note: This abstract was not presented at the meeting. Citation Format: Shyh-Han Tan, Andy Martinez, Anshu Rastogi, Wei Huang, Sreedatta Banerjee, Lakshmi Ravindranath, Denise Young, Amina Ali, Indu Kohaar, Yongmei Chen, Jennifer Cullen, Gyorgy Petrovics, Albert Dobi, David G. McLeod, Jacob Kagan, Sudhir Srivastava, Isabell A. Sesterhenn, Inger L. Rosner, Shiv Srivastava, Alagarsamy Srinivasan. Tumor antigens Fetuin-A and Secreted Protein Acidic and Rich in Cysteine (SPARC) Autoantibodies as diagnostic and prognostic biomarkers in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3296.