Genetic and Epigenetic Variations of HPV52 in Cervical Precancer
Abstract
:1. Introduction
2. Results
2.1. CpG Methylation Determined by Pyrosequencing
2.2. CpG Methylation Determined by Next-Generation Sequencing (NGS)
2.3. Sanger Sequencing Analysis of Complete HPV52 Genomes
2.4. HPV52 Phylogenetic Analysis of 106 Isolates
2.5. Association of Variant Lineage and Disease Status
2.6. Analysis of Nucleotide Variations at CpG Sites
3. Discussion
4. Materials and Methods
4.1. Study Design and Population
4.2. Sodium Bisulfite Treatment
4.3. Pyrosequencing
4.4. Next-Generation Sequenicng (NGS)
4.5. Bioinformatic Analysis of NGS Reads
4.6. Sequencing of HPV52 Complete Genomes
4.7. Construction of Phylogentic Tree
4.8. Statistical Analyses
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Disclaimer
Abbreviations
HPV | Human papillomavirus |
HR-HPV | High-risk human papillomavirus |
Alpha9 | Alphapapillomavirus species 9 (HPV16-related) |
Alpha7 | Alphapapillomavirus species 7 (HPV18-related) |
CIN3 | Cervical intraepithelial neoplasia grade 3 |
CpG site | CG dinucleotide |
AIS | Adenocarcinoma in situ |
SCC | Squamous cell cancer |
URR | Upstream regulatory region |
OR | Odds ratio |
CI | Confidence interval |
AUC | Area under the curve |
SNP | Single nucleotide polymorphism |
NGS | Next-generation sequencing |
NCR1 | Noncoding region 1 |
VWAS | Viral genome wide association study |
PaP cohort | HPV Persistence and Progression |
KPNC | Kaiser Permanente Northern California |
NCI | National Cancer Institute |
HC2 | Hybrid capture 2 |
NILM | Negative for intraepithelial lesions or malignancy |
bp | Base pair |
ML | Maximum likelihood |
MCMC | Markov chain Monte Carlo |
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Median | Man-Whitney (Wilcoxon Rank Sum) | ROC Curve | 95% CI Interval | Univariate Regression High HPV Methylation vs. Low/Medium Methylation | ||||||
---|---|---|---|---|---|---|---|---|---|---|
Region Name | Genome Position | Control (n = 39) | Case (n = 50) | Difference | p Value | AUC | OR | 95% CI | p Value | |
E7 | c_754 c_776 c_779 c_787 | 1.40 13.20 1.20 5.90 | 1.80 13.30 1.20 6.40 | 0.40 0.10 0.00 0.50 | 0.010910 0.542481 0.771323 0.141489 | 0.6583 0.5379 0.5181 0.5916 | (0.54, 0.78) (0.42, 0.66) (0.39, 0.65) (0.47, 0.71) | 4.64 2.36 0.50 1.99 | (1.88, 11.47) (0.95, 5.89) (0.18, 1.39) (0.82, 4.81) | 0.000886 0.064880 0.182842 0.125934 |
E1 | c_1122 c_1141 | 1.85 6.20 | 1.55 7.55 | −0.30 1.35 | 0.319005 0.057360 | 0.4405 0.6187 | (0.32, 0.56) (0.50, 0.74) | 0.61 1.85 | (0.23, 1.59) (0.76, 4.46) | 0.313096 0.173033 |
L2 | c_4274 c_4283 c_4292 c_4919 c_4926 c_4931 c_4949 | 8.00 18.50 10.90 2.40 4.30 4.40 32.60 | 13.50 17.20 19.90 3.00 5.25 4.70 39.50 | 5.50 −1.30 9.00 0.60 0.95 0.30 6.90 | 0.001171 0.003156 0.001699 0.085078 0.251942 0.295395 0.371808 | 0.7013 0.6831 0.6946 0.6062 0.5710 0.5649 0.5554 | (0.59, 0.82) (0.57, 0.80) (0.58, 0.81) (0.49, 0.72) (0.45, 0.69) (0.45, 0.68) (0.43, 0.68) | 2.44 2.25 2.44 2.25 1.50 1.56 1.38 | (1.01, 5.86) (0.94, 5.41) (1.01, 5.86) (0.94, 5.41) (0.62, 3.63) (0.63, 3.84) (0.57, 3.35) | 0.046613 0.070045 0.046613 0.070045 0.368990 0.333509 0.478098 |
L1 | c_5606 c_5609 c_5615 c_5621 c_5648 c_5655 c_7098 c_7111 c_7119 | 18.00 15.00 30.20 5.00 26.80 35.90 3.10 5.90 3.40 | 33.20 25.90 48.10 8.05 32.15 51.20 3.90 10.30 5.70 | 15.20 10.90 17.90 3.05 5.35 15.30 0.80 4.40 2.30 | 0.001393 0.007199 0.000257 0.001651 0.034620 0.001799 0.024831 0.016845 0.032968 | 0.6982 0.6667 0.7267 0.6951 0.631 0.6936 0.6397 0.6489 0.6327 | (0.58, 0.81) (0.55, 0.79) (0.62, 0.83) (0.58, 0.81) (0.51, 0.75) (0.58, 0.80) (0.52, 0.76) (0.53, 0.77) (0.51, 0.76) | 3.38 2.64 4.78 2.86 2.08 3.67 1.99 2.76 3.55 | (1.39, 8.17) (1.10, 6.36) (1.94, 11.80) (1.19, 6.90) (0.86, 5.00) (1.51, 8.92) (0.82, 4.81) (1.14, 6.68) (1.46, 8.65) | 0.007037 0.030232 0.000684 0.019101 0.102620 0.004099 0.125934 0.024124 0.005258 |
URR | c_7557 c_7563 | 2.50 2.80 | 2.50 3.05 | 0.00 0.25 | 0.885024 0.423051 | 0.5096 0.553 | (0.37, 0.64) (0.42, 0.68) | 0.81 1.71 | (0.30, 2.19) (0.68, 2.01) | 0.680344 0.579475 |
Median | Man-Whitney (Wilcoxon Rank Sum) | ROC Curve | 95% CI Interval | Univariate Regression High HPV Methylation vs. Low/Medium Methylation | ||||||
---|---|---|---|---|---|---|---|---|---|---|
Region Name | Genome Position | Control (n = 38) | Case (n = 50) | Difference | p Value | AUC | OR | 95% CI | p Value | |
L1 | c_5606 c_5609 c_5615 c_5621 c_5648 c_5655 | 27.36 18.84 40.90 5.34 32.21 48.22 | 30.45 22.11 46.76 6.26 37.07 52.92 | 3.09 3.27 5.86 0.92 4.86 4.70 | 0.005258 0.003606 0.003330 0.052489 0.003512 0.005895 | 0.6731 0.6805 0.6821 0.6203 0.681 0.6708 | (0.56, 0.79) (0.56, 0.80) (0.57, 0.80) (0.50, 0.74) (0.57, 0.80) (0.55, 0.79) | 3.38 1.92 3.67 1.92 2.86 2.86 | (1.39, 8.17) (0.80, 4.61) (1.51, 8.92) (0.80, 4.61) (1.19, 6.90) (1.19, 6.90) | 0.007037 0.146627 0.004099 0.146627 0.019101 0.019101 |
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Bee, K.J.; Gradissimo, A.; Chen, Z.; Harari, A.; Schiffman, M.; Raine-Bennett, T.; Castle, P.E.; Clarke, M.; Wentzensen, N.; Burk, R.D. Genetic and Epigenetic Variations of HPV52 in Cervical Precancer. Int. J. Mol. Sci. 2021, 22, 6463. https://doi.org/10.3390/ijms22126463
Bee KJ, Gradissimo A, Chen Z, Harari A, Schiffman M, Raine-Bennett T, Castle PE, Clarke M, Wentzensen N, Burk RD. Genetic and Epigenetic Variations of HPV52 in Cervical Precancer. International Journal of Molecular Sciences. 2021; 22(12):6463. https://doi.org/10.3390/ijms22126463
Chicago/Turabian StyleBee, Katharine J., Ana Gradissimo, Zigui Chen, Ariana Harari, Mark Schiffman, Tina Raine-Bennett, Philip E. Castle, Megan Clarke, Nicolas Wentzensen, and Robert D. Burk. 2021. "Genetic and Epigenetic Variations of HPV52 in Cervical Precancer" International Journal of Molecular Sciences 22, no. 12: 6463. https://doi.org/10.3390/ijms22126463