Identification of a Three-gene Signature Acting as a Novel Prognostic Biomarker in Intrahepatic Cholangiocarcinoma Patients

Abstract

Background: Intrahepatic cholangiocarcinoma (iCCA) patients have poor outcomes due to the lack of biomarkers for the selection of treatment options. The present study was conducted to find biomarkers with independent prognostic vaule in iCCA patients. Methods: Gene transcriptome profiles of E-MTAB-6389, TCGA-CHOL and GSE26566 were obtained from ArrayExpress, The Cancer Genome Atlas and the Gene Expression Omnibus databases, respectively. Bioinformatic analyses were performed to screen novel biomarkers for predicting the prognosis of iCCA patients. Using multivariate Cox regression analyses, a 3-gene signature (BTD-FER-COL12A1) with potential prognostic value was identified and validated in both a training cohort and two validation cohorts. Results: A total of 177 iCCA patients were included in this study. From the key gene modules significantly associated with liver cirrhosis and overall survival (OS) of iCCA patients, we identified 89 hub genes for functional analyses. Cox-regression analyses in both the training and validation cohort indicate that FER, COL12A1 and BTD were independent risk factors for iCCA patients. A 3-gene signature (BTD-FER-COL12A1) with independent prognostic value in iCCA patients was validated in the training cohort, as well as in two validation cohorts. In terms of predicting the prognosis of iCCA patients, the receiver operating characteristics (ROC) curves showed that this 3-gene signature had superior prediction power to BTD, FER, and COL12A1 alone, as well as known biomarkers (MUC1, MUC13) of iCCA. Immunohistochemical staining of samples from The Human Protein Atlas showed that FER and COL12A1 were positively expressed in iCCA tissue, although BTD was not, while none of these genes was detected in normal tissue. These findings were consistent with the expression status of BTD, FER and COL12A1 at the transcriptional level. In addition, we found that FER and COL12A1 were significantly associated with the degree of infiltration by tumor-infiltrating immune cells. Conclusion: We discovered a three-gene signature with independent prognostic value as a novel biomarker for prediction prognosis of iCCA patients. Our findings may help to find novel therapeutic targets for precision treatment of iCCA.