Dna Methylation Changes Prevalence And Risk Factors Associated With Hpv Genotypes Among Ethiopian Women Diagnosed For Cervical Cancer

Cervical cancer is the second most common among cancers in Ethiopia with an incidence ofrnmore than 6000 cases and around 5000 deaths per year. Infection by high risk humanrnpapillomavirus (hrHPV) is the major risk factor for cervical cancer with almost all cases beingrninfected. HPV infection is a very common sexually transmitted infection that majority ofrnsexually active women acquire. Most of the infected women however clear the infectionrnspontaneously in short time while it persists and causes cervical cancer in only small portion ofrnthe infected women. Various factors are known to determine the outcome of the infection butrnwith scarce information on the mechanisms. DNA methylation changes in both human genes andrnHPV genes are among the biological events associated with cervical cancer progression. Thisrnstudy was aimed at determining prevalence of hrHPV, socio-demographic risk factors forrncervical cancer and epigenetic changes associated with cervical cancer and evaluate theirrnpotential as diagnostic markers. The study was conducted as an observational case-control studyrnby taking records of various risk factors and clinical information along with cervical cell samplesrnfor hrHPV testing and DNA methylation analysis. The human EPB41L3 gene promoter regionrnand HPV L1 and L2 regions were PCR amplified from bisulphite converted DNA. The PCRrnamplicons were then pyrosequenced and proportion of converted cytosine is measured andrnmeans of the targeted CpG sites methylation were recorded. Prevalence of both hrHPV andrndemographic risk factors were compared among women with cervical lesions (cases) and womenrnwith normal cytology (controls) to determine associations with various stages of cervical cancer.rnThe DNA methylation assays were evaluated and compared for their performance using RecieverrnOperating Characteristics (ROC) curve analysis. From a total of 135 women, 96 had cervical cellrnlesions ranging from CIN1 to invasive cancer (cases) and 39 had no lesion (controls). Parity wasrnhigher in cases 5.44(±3.01) than in controls 2.03(±2.04). Cases started sexual intercourse earlier,rnat mean age of 16.57(±4.04) years, than the controls 20.18(±4.24) years. Hormonal contraceptivernuse showed no significant difference among cases and controls. HPV DNA was detected inrn79(82.3%) of cases and 7(17.9%) of controls from which 77(80.2%) of cases and 6(15.4%) ofrncontrols were hrHPV. HPV16 was the most prevalent virus constituting 84% of all hrHPVrnpositive cases and 33.3% of hrHPV positive controls. HPV45, HPV18 and HPV31 were detectedrnin 17.7%, 5.2% and 3.8% respectively of the hrHPV positive cases. Level of methylation in bothrnhuman and hrHPV DNA was found to be higher in higher grade lesions than in low grade lesionsrn(CIN1) and normal cervical cells. Methylation assays, both EPB41L3 promoter methylation andrnS5 score discriminated normal and CIN1 from CIN3 or worse lesions with sensitivity andrnspecificity of greater than 95%. In conclusion, higher parity and earlier age at first sexualrnintercourse are among the factors that put women at higher risk of cervical cancer in addition tornhrHPV infection. HPV16 is the most prevalent (69.8%) hrHPV type followed by HPV45rn(14.6%) in Ethiopian women with cervical lesions. Methylation levels of the human EPB41L3rnpromoter region and HPV L1 and L2 regions are potential biomarker to improve precision ofrndiagnosing the cancer and targeting for therapy. EBP41L3 methylation alone discriminatedrnnormal and CIN1 cells from CIN3 or worse lesions with 95% sensitivity and 96% specificityrnwhile S5 detected with 96% sensitivity and 95% specifi

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