Abstract
Background: Invasive cervical cancer (ICC) and its premalignant phase (cervical intraepithelial neoplasia; CIN1-3) are distinguished by gynecologic and pathologic examination, yet no current methodologies can predict precancerous lesions that are destined to progress to ICC. Thus, development of reliable assays to assess patient prognosis is much needed.Methods: Human papillomavirus (HPV) DNA methylation is significantly altered in cervical disease. Using an HPV enrichment approach and next-generation DNA sequencing, methylation status was characterized in a case-case comparison of CIN (n = 2 CIN1; n = 2 CIN2; n = 20 CIN3) and ICC (n = 37) samples. Pyrosequencing validated methylation changes at CpGs of interest in a larger sample cohort (n = 61 CIN3; 50 ICC).Results: Global viral methylation, across HPV types, was significantly higher in ICC than CIN3. Average L1 gene methylation in 13 different HPV types best distinguished CIN3 from ICC. Methylation levels at individual CpG sites as a quantitative classifier achieved a sensitivity and specificity of >95% for detecting ICC in HPV 16 samples. Pyrosequencing confirmed significantly higher methylation of these CpGs in E1 of HPV 16 in ICC compared with CIN3.Conclusions: Global HPV methylation is significantly higher in ICC than CIN3, with L1 gene methylation levels performing best for distinguishing CIN3 from ICC. Methylation levels at CpGs in the E1 gene of HPV 16 (972, 978, 1870, and 1958) can distinguish between CIN3 and ICC.Impact: Higher methylation at specific E1 CpGs may associate with increased likelihood of progression to ICC in HPV 16-positive CIN3 lesions. Cancer Epidemiol Biomarkers Prev; 26(4); 642-50. ©2017 AACR.
Highlights
Persistent infection with high-risk human papillomavirus (HPV) types is essential for the development of cervical cancer and its precursor, cervical intraepithelial neoplasia grade 3 (CIN3)
Impact: Higher methylation at specific E1 CpGs may associate with increased likelihood of progression to Invasive cervical cancer (ICC) in HPV 16–positive CIN3 lesions
We identified 13 unique HPV types among the 61 samples (Supplementary Fig. S3) with each sample positive for 1–3 HPV types (>1 types were more common in CIN than ICC)
Summary
Persistent infection with high-risk human papillomavirus (HPV) types is essential for the development of cervical cancer and its precursor, cervical intraepithelial neoplasia grade 3 (CIN3). Not all precancerous lesions progress to invasive cancer. Lesions in up to 30% to 40% of patients with CIN2-3 will spontaneously regress [1, 2], whereas progression of CIN3 to invasive cervical cancer (ICC) is estimated to occur in
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