Diagnostic Potential of Zinc Finger Protein-Specific Autoantibodies and Associated Linear B-Cell Epitopes in Colorectal Cancer

Abstract

Colorectal cancer is one of the most common cancers worldwide with almost 700,000 deaths every year. Detection of colorectal cancer at an early stage significantly improves patient survival. Cancer-specific autoantibodies found in sera of cancer patients can be used for pre-symptomatic detection of the disease. In this study we assess the zinc finger proteins ZNF346, ZNF638, ZNF700 and ZNF768 as capture antigens for the detection of autoantibodies in colorectal cancer. Sera from 96 patients with colorectal cancer and 35 control patients with no evidence of cancer on colonoscopy were analysed for the presence of ZNF-specific autoantibodies using an indirect ELISA. Autoantibodies to individual ZNF proteins were detected in 10–20% of colorectal cancer patients and in 0–5.7% of controls. A panel of all four ZNF proteins resulted in an assay specificity of 91.4% and sensitivity of 41.7% for the detection of cancer patients in a cohort of non-cancer controls and colorectal cancer patients. Clinicopathological and survival analysis revealed that ZNF autoantibodies were independent of disease stage and did not correlate with disease outcome. Since ZNF autoantibodies were shared between patients and corresponding ZNF proteins showed similarities in their zinc finger motifs, we performed an in silico epitope sequence analysis. Zinc finger proteins ZNF700 and ZNF768 showed the highest sequence similarity with a bl2seq score of 262 (E-value 1E-81) and their classical C2H2 ZNF motifs were identified as potential epitopes contributing to their elevated immunogenic potential. Our findings show an enhanced and specific immunogenicity to zinc finger proteins, thereby providing a multiplexed autoantibody assay for minimally invasive detection of colorectal cancer.

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DNA‑methylated gene markers for colorectal cancer in TCGA database

“…Considering the clinical significance of methylation regulatory genes, Kaplan-Meier survival analysis was performed and the candidate key genes (NXPE4, REP15 and ZNF726), whose aberrant expression was linked to CRC prognosis, screened. ZNF proteins, including ZNF346, ZNF638, ZNF700 and ZNF768, are capture antigens for detecting autoantibodies in CRC (31). In addition, DNA methylation biomarkers of the ZNF gene family, combined with other genes, may be useful in the clinical setting for head and neck squamous cell carcinoma (32).…”

Gene expression differences among different MSI statuses in colorectal cancer

“…The following two predicted genes turn out to encode zinc finger proteins ZC4H2 and ZCCHC2. Zinc finger proteins have been widely reported to be abnormally functioning in colorectal cancer patients . As for its contribution to microsatellite instability, recent publications confirmed that such genes may involve in the regulation and maintenance of normal microsatellite status and patients with different MSI status may have different drug reactivity against zinc finger protein targeted drugs, implying the potential relationship between zinc finger proteins and colorectal cancer MSI status.…”