Serum Anti-BRAT1 is a Common Molecular Biomarker for Gastrointestinal Cancers and Atherosclerosis

Liubing Hu; Jiyue Liu; Hideaki Shimada; Masaaki Ito; Kazuo Sugimoto; Takaki Hiwasa; Qinghua Zhou; Jianshuang Li; Si Shen; Hao Wang

doi:10.3389/fonc.2022.870086

Serum Anti-BRAT1 is a Common Molecular Biomarker for Gastrointestinal Cancers and Atherosclerosis

Front Oncol. 2022 May 17:12:870086. doi: 10.3389/fonc.2022.870086. eCollection 2022.

Authors

Liubing Hu^{1

2

3}, Jiyue Liu^{1

4}, Hideaki Shimada⁵, Masaaki Ito⁵, Kazuo Sugimoto^{6

7}, Takaki Hiwasa⁶, Qinghua Zhou^{2

3}, Jianshuang Li^{2

3}, Si Shen^{1

8}, Hao Wang^{1

4

6}

Affiliations

¹ Stroke Center, The First Affiliated Hospital, Jinan University, Guangzhou, China.
² The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, China.
³ College of Life Science and Technology, Jinan University, Guangzhou, China.
⁴ Department of Anesthesiology, The First Affiliated Hospital, Jinan University, Guangzhou, China.
⁵ Department of Gastroenterological Surgery and Clinical Oncology, Toho University Graduate School of Medicine, Tokyo, Japan.
⁶ Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chiba, Japan.
⁷ Department of Neurology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
⁸ Department of Radiology, Medical Imaging Center, The First Affiliated Hospital, Jinan University, Guangzhou, China.

Abstract

Atherosclerosis (AS) and cancers are major global causes of mortality and morbidity. They also share common modifiable pathogenesis risk factors. As the same strategies used to predict AS could also detect certain cancers, we sought novel serum antibody biomarkers of cancers in atherosclerotic sera sampled by liquid biopsy. Using serological antigen identification by cDNA expression cloning (SEREX) and western blot, we screened and detected the antigens BRCA1-Associated ATM Activator 1 (BRAT1) and WD Repeat Domain 1 (WDR1) in the sera of patients with transient ischemic attacks (TIA). Amplified luminescence proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) established the upregulation of serum BRAT1 antibody (BRAT1-Abs) and WDR1 antibody (WDR1-Abs) in patients with AS-related diseases compared with healthy subjects. ROC and Spearman's correlation analyses showed that BRAT1-Abs and WDR1-Abs could detect AS-related diseases. Thus, serum BRAT1-Abs and WDR1-Abs are potential AS biomarkers. We used online databases and AlphaLISA detection to compare relative antigen and serum antibody expression and found high BRAT1 and BRAT1-Abs expression in patients with GI cancers. Significant increases (> 0.6) in the AUC for BRAT1-Ab vs. esophageal squamous cell carcinoma (ESCC), gastric cancer, and colorectal cancer suggested that BRAT1-Ab exhibited better predictive potential for GI cancers than WDR1-Ab. There was no significant difference in overall survival (OS) between BRAT1-Ab groups (P = 0.12). Nevertheless, a log-rank test disclosed that the highest serum BRAT1-Ab levels were associated with poor ESCC prognosis at 5-60 weeks post-surgery. We validated the foregoing conclusions by comparing serum BRAT1-Ab and WDR1-Ab levels based on the clinicopathological characteristics of the patients with ESCC. Multiple statistical approaches established a correlation between serum BRAT1-Ab levels and platelet counts. BRAT1-Ab upregulation may enable early detection of AS and GI cancers and facilitate the delay of disease progression. Thus, BRAT1-Ab is a potential antibody biomarker for the diagnosis of AS and GI cancers and strongly supports the routine clinical application of liquid biopsy in chronic disease detection and diagnosis.

Keywords: BRAT1; antibody biomarker; atherosclerosis; gastrointestinal cancer; liquid biopsy.