Application Value Of High-risk HPVE6/E7 MRNA Detection In Stratified Management Of Cervical Lesions

Background and Objective Cervical cancer poses a serious threat to the lives and health of women around the world.Sustained infection of high-risk human papillomavirus?HR-HPV?is a necessary condition for cervical cancer,but it may take longer from HR-HPV infection to cervical precancerous lesions to cervical cancer.For years or even decades.Therefore,an effective screening program can detect precancerous lesions early and provide intervention to prevent cervical cancer.The earliest clinically applied Pap smear significantly reduced the incidence and mortality of cervical cancer worldwide.However,due to certain defects in the Pap smear and the results are affected by many factors,it still has lower sensitivity and higher false negative rate.With the emergence of liquid-based cytology technology,the problems associated with traditional Pap smears have been improved and solved to some extent,and the accuracy of diagnosis is much higher than that of traditional smears.With the in-depth study of the etiology of cervical cancer,some scientists have suggested that high-risk HPV infection is a necessary condition for the development of cervical cancer and precancerous lesions.However,HPV-DNA testing can only detect the presence of high-risk HPV infections and does not detect transient or persistent infections.In recent years,studies on the carcinogenic mechanism of high-risk HPV have shown that the E6 and E7 oncogenes in the HPV genome play an important role in tumorigenesis.These two oncogenes encode E6 and E7 proteins,and these two protein expressions can be separately Binding to the tumor suppressor genes p53 and Rb causes uncontrolled cell proliferation leading to precancerous lesions and cancer.In response to the HPV carcinogenic mechanism,the US Food and Drug Administration?FDA?approved the Aptima detection technology in 2012.This method can detect not only the presence of high-risk HPV infection,but also whether HPV infection is active or not.Progress and prognosis are predicted and evaluated.In this paper,Aptima was performed in patients with positive HPV-DNA screening to investigate the diagnostic efficacy and expression level of HPVE6/E7 mRNA in different grades of cervical lesions,thus providing a basis for stratified management of cervical lesions.Materials and Methods Collection of gynecological clinics of the Second Affiliated Hospital of Zhengzhou University?Henan Province Cervical Cancer Prevention and Treatment Center?from June 2017 to June 2018,due to contact bleeding,irregular vaginal bleeding,vaginal discharge,or routine physical examination.The 381 patients with positive screening were included in the study.Cervical cytology and HPVE6/E7mRNA were detected in all 381 patients positive for HC₂ screening.If the cytology was positive,cervical biopsy was performed under the guidance of colposcopy,and biopsy histopathology was used as a diagnosis.gold standard.The positive rate and expression level of HPVE6/E7 mRNA were compared between different cytology and histology.The diagnostic efficacy of CIN2+was compared between HPVE6/E7mRNA and HC₂.Result ?1?Comparative analysis of HPVE6/E7 mRNA positive rate and expression level in different cytopathology he cytological results of 381 patients were NILM,ASCUS,LSIL,ASC-H,HSIL,and CC,respectively,65?17.06%?,134?35.17%?,35?9.19%?,and 72?18.90%?,57 cases?14.96%?,18 cases?4.72%?.The positive rates of HPVE6/E7mRNA were 30.76%?48.51%?45.71%?51.39%?70.18%and 72.22%,respectively.The positive rate of HPVE6/E7 mRNA in different cytological types was statistically significant??²=22.88,P<0.05?.The expression levels of HPVE6/E7 mRNA?median?interquartile range Q25,Q75??were:0.61?0.24,24.07?,0.96?0.43,113.74?,0.89?0.68,224.98?,67.9?0.86,275.14?,328.09?0.90,769.90?,211.38?0.91,1306.92?,The rank sum test was used for multiple quantitative data.The difference of HPVE6/E7 mRNA expression in different cytological types was statistically significant?F=87.61,P<0.05?.?2?Comparative analysis of HPVE6/E7 mRNA positive rate and expression level in different histopathology:316 cases of cytological abnormalities confirmed by colposcopy biopsy,chronic cervicitis,low grade squamous intraepithelial lesion?CIN1?,high grade squamous intraepithelial lesion?CIN2?,high grade squamous intraepithelial lesion?CIN3?),cervical squamous cell carcinoma were 102 cases?32.28%?,82 cases?25.95%?,48?15.19%?,63?19.94%?,21?6.65%?;the positive rate of HPVE6/E7 mRNA was40.20%,36.59%,72.92%,74.60%,85.71%,The highest positive rate was in the cervical cancer group,and the lowest was in the CIN1 group.The difference between the whole groups was statistically significant??²=44.03,P<0.05?.The expression level of HPVE6/E7 mRNA?median?interquartile range Q25,Q75??was0.73?0.24,61.61?,0.86?0.43,92.67?,166.49?0.89,289.01?,278.90?0.99,864.45?,278.69?163.24,546.81?,The expression of HPVE6/E7 mRNA in different histopathological types was statistically significant??²=102.74,P<0.05?,and the HPVE6/E7 mRNA load increased with the severity of histopathological results.Further,the expression of cervical invasive carcinoma and CIN3 was the highest,and the two were similar,followed by CIN2,CIN1 and chronic cervicitis with the lowest expression,and the two were similar.?3?Comparative analysis of HPV-DNA loading in different histopathology:316 patients undergoing colposcopy biopsy were HC₂-positive,HPV-DNA loading in cervical inflammation group,CIN1,CIN2,CIN3,and cervical invasive carcinoma?median?interquartile range Q25,Q75??:68.07?20.60,125.94?,42.38?18.03,86.27?,102.18?32.53,203.79?,74.23?20.02,221.76?,106.67?64.23,220.07??The highest load was in the cervical invasive cancer group,followed by the CIN2 group,and the lowest was the CIN1 group.The multi-group rank sum test showed that the HPV-DNA load difference of different grades was statistically significant??²=18.64,P<0.05?.?4?The HPVE6/E7 mRNA expression level and HPV-DNA load Spearman rank correlation analysis showed that there was no significant correlation between HPVE6/E7 mRNA expression level and HPV-DNA load?r=0.022,P>0.05?.?5?The ROC curve was used to analyze the diagnostic efficacy of HPVE6/E7mRNA detection and HC₂ detection in CIN2+lesions.The area under the curve of HPVE6/E7 mRNA detection and HC₂ detection was 0.826[95%CI?0.781,0.871?],0.622[95%CI?0.558,0.685?].The diagnostic threshold for HPVE6/E7mRNA was 165.31 copies/ml.If the HPVE6/E7 mRNA expression level 165.31copies/ml is used as the diagnostic threshold,then the sensitivity,specificity,positive predictive value,negative predictive value,positive ikelihood ratio,and negative likelihood ratio of the diagnostic method for CIN2+ iagnosis at this time They were 80.30%?106/132?,76.09%?140/184?,70.67% 106/150),85.37%?140/164?,3.36,and 0.26,respectively.The HPV-DNA iagnostic threshold was 52.44 pg/ml.If the HPV-DNA load?52.44 pg/ml is sed as the diagnostic threshold,then the sensitivity,specificity,positive redictive value,negative predictive value,positive likelihood ratio,and negative kelihood ratio of the diagnostic method for CIN 2+diagnosis at this time They ere 75.76%?100/132?,52.17%?96/184?,53.19%?100/188?,75.00%?96/128?,1.58,and 0.46,respectively.Conclusions ?1?HPVE6/E7 mRNA positive rate and expression increased with increasing cytopathology and histopathology;?2?HPV-DNA expression load increases with the severity of cervical lesions;?3?There was no significant correlation between HPVE6/E7 mRNA expression evel and HPV-DNA load;?4?The HPVE6/E7 mRNA detection is superior to HPV-DNA detection in the diagnosis of CIN2 and above,and can provide a clinical basis for the stratified management of cervical lesions.