The association between human papillomavirus 16, 18 DNA load and E6 protein expression in cervical intraepithelial neoplasia and cancer

Background: It has been reported that high HPV DNA load and elevated E6 protein expression correlate with cervical cancer, but no epidemiological study has been performed. Objectives: To assess the association between type-specific HPV DNA load and presence of E6 protein in cervical intraepithelial neoplasia and cancer. Study design: This study was a cross-sectional multicenter study performed between 2013 and 2017. A total of 1717 women (normal histopathology: n = 916; CIN1: n = 94; CIN2: n = 63; CIN3: n = 130; SCC: n = 474; adenocarcinoma: n = 40) were included. HPV DNA load and presence of E6 protein were detected. DNA load was measured as log copies/10,000 cells. Results: The HPV16/18-E6 positivity rates increased from negative for DNA to the highest load grade. Compared to the HPV16 DNA negatives, women with low (RR = 31.5, 95% CI = 18.9-52.5), medium-low (RR = 133.5, 95% CI = 77.3-230.7), medium-high (RR = 247.9, 95% CI = 134.9-455.6) and high DNA loads (RR = 677.9, 95% CI = 301.6-1523.7) had increasingly higher relative ratios of HPV16-E6 expression. The association of HPV18-E6 with its DNA load was also significant for low (RR = 27.9, 95% CI = 10.4-74.9), medium-low (RR = 89.0, 95% CI = 32.8-241.3), medium-high (RR = 276.8, 95% CI = 76.7-998.9) and high grade (RR = 441.2, 95% CI = 97.7-1992.4). The positivity rates of both HPV16 DNA and E6 protein increased consistently with the severity of diseases from normal histopathology to SCC. Unlike HPV16, the trends of HPV18 DNA and E6 protein fluctuated consistently among women from normal histopathology to cancer. DNA load in E6-positive women was significantly higher than E6-negative for both types. Conclusions: There is a type-dependent association between HPV16/18 DNA load and E6 protein; our study furthers the understanding of the natural history of cervical cancer.