Abstract
Identification of CRC patients with early-stage disease provides the opportunity for curative local resection. However, robust markers for stage I tumor prediction are yet to be developed. We analyzed RNA-sequencing data of 221 CRC samples using the TCGA dataset to identify novel biomarkers for stage I CRC. We next validated the TCGA finding in an independent GEO cohort of 290 CRC patients and in a third cohort of 110 CRC tumors and matched normal samples. We further performed correlative analysis of ZC3H12A gene expression with clinicopathologic features and disease-free survival. Expression correlation of ZC3H12A with the chemokine ligands was evaluated via Student's t-test. In the TCGA cohort, stage I CRC patients had significantly higher ZC3H12A mRNA expression as compared with the other three stages combined and with the other individual stages in a pairwise manner (P<0.001 for all comparisons). The significant association of ZC3H12A gene expression with stages was further validated in the GEO cohort and in the additional third cohort. In support of these findings, we further found that patients with lower ZC3H12A expression had more aggressive tumor features and shorter disease-free survival. Biologically, ZC3H12A expression was significantly correlated with expression of three chemokine ligands (CXCL1, CXCL2 and CXCL3), suggesting that immune response dysregulation likely contributes to CRC development. Our results demonstrate ZC3H12A's potential role in identification of CRC patients with early-stage disease.