Integrative meta-analysis of gene expression profiles identifies FEN1 and ENDOU as potential diagnostic biomarkers for cervical squamous cell carcinoma

Cervical carcinoma is a global public health burden. Given that it is usually asymptomatic at potentially curative stages, the development of clinically accurate tests is critical for early detection and individual risk stratification. The present study performed an integrative meta-analysis of the transcriptomes from 10 cervical carcinoma cohorts, with the aim of identifying biomarkers that are associated with malignant transformation of cervical epithelium, and establish their clinical applicability. From among the top ranked differentially expressed genes, flap structure-specific endonuclease 1 (FEN1) and poly (U)-specific endoribonuclease (ENDOU) were selected for further validation, and their clinical applicability was assessed using immunohistochemically stained microarrays comprising 110 tissue cores, using p16 and Ki67 staining as the comparator tests. The results demonstrated that FEN1 expression was significantly upregulated in 65% of tumor specimens (P=0.0001), with no detectable expression in the non-tumor tissues. Furthermore, its expression was significantly associated with Ki67 staining in tumor samples (P<0.0001), but no association was observed with p16 expression or the presence of human papilloma virus types 16/18, patient age, tumor grade or stage. FEN1 staining demonstrated lower sensitivity than p16 (69.3 vs. 96.8%) and Ki67 (69.3 vs. 76.3%); however, the specificity was identical to p16 and higher than that of Ki67 (100 vs. 71.4%).ENDOU staining was consistent with the microarray results, demonstrating 1% positivity in tumors and 40% positivity in non-tumor tissues. Gene set enrichment analysis of cervical tumors overexpressing FEN1 revealed its association with enhanced growth factor signaling, immune response inhibition and extracellular matrix remodeling, whereas tumors with low ENDOU expression exhibited inhibition of epithelial development and differentiation processes. Taken together, the results of the present study demonstrate the feasibility of the integrative meta-analysis approach to identify relevant biomarkers associated with cervical carcinogenesis. Thus, FEN1 and ENDOU may be useful diagnostic biomarkers for squamous cervical carcinoma. However, further studies are required to determine their diagnostic performance in larger patient cohorts and validate the results presented here.