High expression of CXCL14 is a biomarker of lung adenocarcinoma with micropapillary pattern.

: Lung adenocarcinoma with micropapillary pattern (MPP) has an aggressive malignant behavior. Limited resection should be avoided because of its high recurrence rate. If adenocarcinoma with MPP is diagnosed preoperatively, the selection of proper treatment is possible. To explore a preoperative biomarker for diagnosing MPP, we here conducted RNA sequencing analysis of 25 clinical samples as the training set, including 6 MPP, 16 other adenocarcinoma subtypes and 3 normal lung tissues. Unsupervised hierarchical clustering analysis suggested a presence of subgroup with MPP showing different gene expression phenotype. We extracted differentially expressed genes with high expression levels in MPP samples, and chose VSIG1, CXCL14 and BAMBI as candidate biomarkers for MPP. RT-qPCR analysis confirmed a significantly higher expression of VSIG1 (P=0.03) and CXCL14 (P=0.02) in MPP than others. In validation set of 4 MPP and 4 non-MPP samples, CXCL14 expression was validated to be significantly higher in MPP than in non-MPP (P=0.04). Comparing a total of 10 MPP and 20 non-MPP samples, the AUC of CXCL14 to distinguish MPP from others was 0.89. The threshold value was 0.0116 corresponding to sensitivity 80% and specificity 90%. In immunostaining of CXCL14, the staining score was significantly higher in MPP cases than others, where not only MPP component but also other components showed heterogeneous staining in adenocarcinoma tissues with MPP. Moreover, higher staining score of CXCL14 significantly associated with poorer prognosis, in all patients (P=0.01) or within cases at stage I-III (P=0.01).In summary, we identified CXCL14 as a possible diagnostic biomarker of MPP.