HPV infection associated DNA damage correlated with cervical precancerous lesions and cancer in the highest area of cervical cancer mortality, Longnan, China

Objectives: This study was to assess whether human papillomavirus (HPV) resulting in genetic instability is one reason for the high incidence and mortality of cervical cancer in Longnan. Methods: Between 2012 and 2016, a total of 346 samples from Longnan were collected and divided into four groups: cervicitis group (n=57), cervical intraepithelial neoplasia I group (CIN I, n=63), CIN II/III group (n=79) and invasive squamous cell carcinoma group (SCC, n=147). HPV E6/E7 mRNA was detected by Quantivirus (R) HPV E6/E7 RNA 3.0 assay (bDNA). The markers of DNA damage response (DDR) - ataxia telangiectasia mutated (ATM) pSer1981, H2AX pSer139 (gamma H2AX), Chk2 pThr68 and P53 - were analyzed by immunohistochemistry. Results: The activation of ATM, gamma H2AX, Chk2 and P53 was increased with increasing severity of cervical lesion. A significant difference of ATM expression in simple infection was also shown accompanied by the cervical lesion. The expression of gamma H2AX between HPV16+ and HPV16- specimens, gamma H2AX and P53 between HPV58+ and HPV58- groups had statistical significance. The expression and copy number of HPV E6/7 mRNA increases with the cervical lesion severity. A significant difference was shown for P53 expression between HPV E6/7 mRNA+ and mRNA- specimens. A close correlation with CHK2 expression for HPV E6/7 mRNA+ and HPV16 E6/7 mRNA+ specimens and gamma H2AX and CHK2 expression for SCC specimens was shown between low and high viral load groups. Conclusions: DDR, HPV genotypes and HPV E6/E7 oncogene expression correlated with the level of dysplasia of cervical lesions. HPV infection resulted in genetic instability may be one reason for the high incidence and mortality in Longnan.