Differentially Expressed Genes in Matched Normal, Cancer, and Lymph Node Metastases Predict Clinical Outcomes in Patients With Breast Cancer.

Abstract

Genome-wide screening of transcriptional changes among normal, cancer, and nodal metastases provides insights into the molecular basis of breast cancer (BC) progression and metastasis. To identify transcriptional changes and differentially expressed genes (DEGs) in the metastatic progression of BC and to determine the prognostic role of these DEGs in clinical outcome, we compared transcriptome profiling in matched normal, cancer, and lymph node metastatic tissues of 7 patients with estrogen receptor-positive, HER2-negative BC by using massive parallel RNA sequencing. The global profiles of gene expression in cancer and nodal metastases were highly correlated (r=0.962, P<0.001). In 6 (85.8%) patients, cancer and corresponding nodal metastases from the same patient clustered together. We identified 1522 and 664 DEGs between normal and cancer and between cancer and nodal metastases, respectively. The DEGs in normal versus cancer and cancer versus nodal metastases were significantly clustered in 1 and 8 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, respectively. The chemokine signaling pathway was the most significant pathway in the cancer-to-nodal metastasis transition (false discovery rate=2.15E-13). The expression of 2 dysregulated RAC2 and PTGDS genes was confirmed by quantitative real-time polymerase chain reaction and immunohistochemistry. Interestingly, the lower RAC2 and PTGDS expression were associated with significantly worse disease-free survival in patients with BC. Our results show a high concordance of gene expression in BC and their nodal metastases, and identify DEGs associated with the metastatic progression of BC. The DEGs identified in this study represent novel biomarkers for predicting the prognosis of patients with BC.