Table 1. Published Studies of Human Papillomavirus DNA Methylation.
| First Author (Year) | Method | Specimen Type | Sample Size (Cases/Controls) | Outcomes | Location and No. of CpGs |
|---|---|---|---|---|---|
| Methylation of CpG Sites within the URR Associated with Asymptomatic and Low-grade Infections | |||||
| Badal (2003) | MS-restriction digestion and bisulfite sequencing | Exfoliated cervical cells and FFPE biopsy samples | 56/25 | NILM, CIN1-3. SCC | URR (11) |
| Hublarova (2009) | MS-restriction digestion | Exfoliated cervical cells and fresh frozen biopsies | 120/218 | NILM, CIN1-CIN3, ICC | URR (6) |
| Piyathilake (2011) | Pyrosequencing | Exfoliated cervical cells | 30/45 | ≤CIN1, CIN2+ | URR (6) |
| Xi (2011) | Bisulfite Sequencing | Exfoliated cervical cells | 94/117 | < CIN2/3, CIN2/3 | URR (11) |
| Mazumder (2011) | MS-restriction digestion | Fresh frozen biopsies | 205/34 | CIN1-3, ICC | URR (NS) |
| Methylation of CpG Sites within the URR, particularly in E2 Binding sites, is Associated with High-grade Lesions and Cancer | |||||
| Bhattacharjee (2006) | MS-restriction digestion and bisulfite sequencing | Exfoliated cervical cells and fresh frozen biopsies | 57/15 | NILM, SCC | URR (11) |
| Hong (2008) | Pyrosequencing | Exfoliated cervical cells | 14/56 | NILM, CIN1-3, ICC | URR (8) |
| Ding (2009) | Bisulfite Sequencing | Cervical scrapes/biopsy tissues | 36/17 | LSIL, HSIL, SCC | URR (15) |
| Vinokurova & von Knebel Doeberitz (2011) | LCM, Bisulfite Sequencing, COBRA | FFPE tissue sections | 40/3 | NILM, LSIL, HSIL | URR (16) |
| Snellenberg (2011) | Methylation Independent PCR, Luminex xMap | FFPE biopsy samples, exfoliated cervical cells | 48/17 | NILM, CIN3, SCC | E2 binding sites, URR (3) |
| Methylation of L1 is Associated with High-grade Lesions and Cancer | |||||
| Kalantari (2004) | Bisulfite Sequencing | Not specified | 64/51 | NILM, CIN1-3, ICC | 3′ L1 – URR (19) |
| Brandsma (2009) | Bisulfite Sequencing | Cervical cells (PreservCyt) | 9/4 | NILM, ASC-US, LSIL, CIN1-3 | Genome (113) |
| Fernandez (2009) | Bisulfite sequencing and MSP | Not specified | 70/17 | NILM, CIN1-3, SCC | Genome (110; BS.) L2/L1 (BS; MSP) |
| Kalantari (2009) | LCM, bisulfite sequencing | FFPE biopsy samples | 5/2 | NILM, ICC | 3′ end of L1 – URR (19) |
| Kalantari (2010) | Bisulfite sequencing | Exfoliated cervical cells | 21/0 | LSIL, HSIL | 3′ L1 (4) |
| Sun (2011) | Epityper and Pyrosequencing | Exfoliated cervical cells | 39/46 | NILM, LSIL/CIN1, CIN2/3, ICC | L1 – URR (32) |
| Mirabello (2012) | Pyrosequencing | Exfoliated cervical cells | 65/34 | Cleared HPV, persistent HPV, CIN3 | Genome (67) |
| Mirabello (2012) | Pyrosequencing | Exfoliated cervical cells | 181/95 | Cleared HPV, persistent HPV, CIN2+ | Genome (66) |
| Methylation of Other HPV Types is Associated with High-grade Lesions and Cancer | |||||
| Badal (2004) | Bisulfite Sequencing | Not specified | 6/5 | NILM, ICC | L1 – URR (39) |
| Turan (2006) | Bisulfite sequencing | Cervical smears/tumor biopsies | 13/11 | NILM, ASC-US, LSIL, HSIL, SCC | L1 – URR (31) |
| Fernandez (2009) | Bisulfite sequencing, MSP for E2 | Not specified | 29/10 | NILM, CIN1-3, SCC | Genome (168) |
| Wentzensen (2012) | Pyrosequencing | Exfoliated cervical cells | HPV18: 40/42 | <CIN2/ASCUS, CIN3 | Genome (106) |
| HPV31: 45/43 | <CIN2/ASCUS, CIN3 | Genome (80) | |||
| HPV45: 12/11 | <CIN2/ASCUS, CIN3 | Genome (105) | |||
Abbreviations: ASC-US, Atypical squamous cells of undetermined significance; BS, Bisulfite sequencing; CIN, Cervical intraepithelial neoplasia; COBRA, Combined bisulfite restriction analysis; E2, E2 gene of human papillomavirus; FFPE, Formalin-fixed, paraffin-embedded; HSIL, High-grade intraepithelial lesion; HPV; Human papillomavirus; ICC, Invasive cervical cancer; L1, L1 gene of human papillomavirus; LCM, Laser-capture microdissection; LSIL, Low-grade intraepithelial lesion; MS, Methylation sensitive; MSP, Methylation specific PCR; NILM, Negative for intraepithelial lesion or malignancy; PCR, Polymerase chain reaction; SCC, Squamous cervical cancer; URR, Upstream regulatory region