Table 2.
Meta-analysis of proportion of HPV methylated samples for different genotypes and genes for ≤CIN1/LSIL vs. ≥CIN2/HSIL. ≤CIN1/LSIL: Normal/ASCUS/LSIL/CIN1. ≥CIN2/HSIL: CIN2/CIN3/HSIL/ICC. The grade was defined by histology; if this was not available, cytology was used.
| Author, year | Cut-off | CpG | Study size | ≤CIN1/LSIL% (N/N) | ≥CIN2/HSIL% (N/N) |
|---|---|---|---|---|---|
| HPV16 L1 | % | % | |||
| Brentnall 2014 | >0% | L1 (bp6367, 6389) | 556 | 90.1 (210/233) | 97.8 (326/323) |
| Qiu 2015 (1) | >10% | L1 (bp5602, 5608, 5611, 5617) | 114 | 40.5 (17/42) | 91.6 (66/72) |
| Qiu 2015 (2) | >10% | L1 (bp7136, 7145) | 81 | 34.3 (11/32) | 89.8 (44/49) |
| Simanaviciene 2015 | >0% | L1 (bp7136, 7145) | 157 | 2.6 (1/39) | 24.6 (29/118) |
| Gasperov 2015 | >0% | L1 (bp7091, 7136, 7145, 7145) | 16 | 30 (3/10) | 33.3 (2/6) |
| Kalantari 2014 | >0% | L1/L2 (bp 5602–7270) | 63 | 13.8 (4/29) | 50 (17/34) |
| Lorincz 2013 | >0% | L1 (bp 6367,6389) | 73 | 100 (48/48) | 100 (25/25) |
| Wang 2017 | >0% | L1 (bp 7089–7268) | 100 | 16.6 (5/30) | 50 (35/70) |
| Total N – n/N* | 1160 | 299/463 | 534/697 | ||
| Pooled estimate (95% CI) | 44.4 (16.0–74.1) | 72.7 (47.8–92.2) | |||
| I2 (95%CI) | 97.61 (93.2–99.3) | 97.2 (93.3–99.3) | |||
| tau2 (95%CI) | 0.18 (0.07–0.75) | 0.11 (0.04–0.41) | |||
| HPV 16 L2 | |||||
| Brentnall 2014 | >0% | L2 (bp4238, 4259, 4275) | 556 | 29.3 (68/233) | 55 (178/323) |
| Kalantari 2014 | >0% | L1/L2 (bp 5602–7270) | 63 | 13.8 (4/29) | 50 (17/34) |
| Lorincz 2013 | >0% | L2 (bp 4238, 4247, 4259, 4268, 4275) | 73 | 79 (38/48) | 96 (24/25) |
| Total N – n/N | 692 | 110/310 | 219/382 | ||
| Pooled Estimate (95% CI) | 40.1 (7–79.3) | 61.8 (43.9–78.2) | |||
| I2 (95%CI) | 96.9 (88.1–99.9) | 85.2 (39.6–99.7) | |||
| tau2 (95%CI) | 0.12 (0.03–5.12) | 0.02 (0.00–1.04) | |||
| HPV16 LCR | |||||
| Badal 2003 | >0% | 5′ LCR, Enh, E6 Prom | 81 | 42.1 (16/38) | 9.3 (4/43) |
| Bhattarcharjee 2006 | >0% | 5′LCR (bp7289-7540) | 72 | 4 (6/15) | 54.4 (31/57) |
| Ding 2009 | >0% | 5′LCR, Enh, E6 Prom (bp7426-58) | 53 | 5.9 (1/17) | 41.7 (15/36) |
| Dutta 2015 | >0% | Enh (bp7535-7694), E6 Prom | 215 | 4.1 (41/93) | 44.3 (54/122) |
| Hublarova 2009 | >0% | E6 Prom (bp7851-7559) | 141 | 81 (17/21) | 35.8 (43/120) |
| Gasperov 2015 | >0% | 3′LCR, Enh, Prom (bp7091-58) | 12 | 50 (3/6) | 33.3 (2/6) |
| Simanaviciene 2015 | >0% | 5′LCR, Enh, Prom (bp7270-58) | 157 | 2.7 (1/39) | 23.7 (28/118) |
| Xi 2011 | >0% | 3′LCR, Enh, Prom (bp7535-58) | 211 | 44.9 (53/117) | 35.6 (34/94) |
| Snellenberg 2012 | >0% | E2BS1 (bp 7370–7383) | 65 | 11.8 (2/17) | 64.6 (31/48) |
| Hong 2008 | >0% | Enh, Prom (bp7676-58) | 70 | 48.4 (15/31) | 71.8 (28/39) |
| Lorincz 2013 | >0% | Prom (bp31-58) | 73 | 90 (43/48) | 92 (23/25) |
| Wang 2017 | >0% | 3′L1, 5′LCR, Enh, Prom (bp7089-58) | 101 | 8.8 (3/34) | 32.8 (22/67) |
| Total N – n/N | 1251 | 201/476 | 315/775 | ||
| Pooled Estimate (95% CI) | 37.5 (20.2–56.5) | 44.5 (30.9–58.5) | |||
| I2 (95%CI) | 93.4 (86.4–97.7) | 92.8 (85.1–97.6) | |||
| tau2 (95%CI) | 0.09 (0.05–1.04) | 0.05 (0.02–0.16) | |||
| HPV 18 L1/L2 | |||||
| Simanaviciene 2015 | >0% | L1 (bp6916-7122) | 21 | 18.2 (2/11) | 80 (8/10) |
| Gasperov 2015 | >0% | L1 (bp7017-7140) | 21 | 100 (9/9) | 92.3 (12/13) |
| Brentnall 2014 | >0% | L2 (bp4256-4282) | 201 | 70.9 (91/128) | 84.1 (61/73) |
| Kalantari 2014 | >0% | L1/L2 (bp5602-7270) | 14 | 14.3 (1/7) | 85.7 (6/7) |
| Total N – n/N | 258 | 103/155 | 87/103 | ||
| Pooled Estimate (95% CI) | 52.6 (13.8–89.8) | 86.0 (77.7–92.8) | |||
| I2 (95%CI) | 90.6 (67.7–99.4) | 0.0 (0.0–75.4) | |||
| tau2 (95%CI) | 0.14 (0.03–2.30) | 0.00 (0.00–0.05) | |||
| HPV18 LCR | |||||
| Simanaviciene 2015 | >0% | LCR (LCR5′, Prom, Enh) | 21 | 0 (0/13) | 20 (2/8) |
| Total N – n/N | 21 | 0/13 | 2/8 | ||
| HPV 31 L1/L2 | |||||
| Brentnall 2014 | >0% | L1 (bp6352, 6364) | 202 | 59.6 (62/104) | 85.7 (84/98) |
| Kalantari 2014 | >0% | L1/L2 (bp5518-5692) | 15 | 0 (0/7) | 50 (4/8) |
| Total N – n/N | 217 | 62/111 | 88/106 | ||
| Pooled Estimate (95% CI) | 33.6 (0.0–87.1) | 73.7 (34.4–99.3) | |||
| I2 (95%CI) | 89.6 (47.6–100) | 89.6 (47.6–100) | |||
| tau2 | 0.14 (0.01–100) | 0.06 (0–78.5) | |||
| HPV 45 L1/L2 | |||||
| Kalantari 2014 | >0% | L1/L2 (bp4795-7135) | 12 | 0 (0/1) | 80 (8/10) |
| Total N – n/N | 12 | 0/1 | 8/10 | ||
| HPV 52 L1 | |||||
| Murakami 2013 | >0% | L1 (bp5606-7120) | 54 | 15 (2.6/17) | 44.7 (17/37) |
| Total N – n/N | 54 | 2.6/17 | 17/37 | ||
| HPV 52 LCR | |||||
| Murakami 2013 | >0% | LCR (LCR5′, Prom, Enh) | 54 | 2.5 (0.4/17) | 2.4 (0.9/37) |
| Total N – n/N | 54 | 0.4/17 | 0.9/37 | ||
| HPV 58 L1 | |||||
| Murakami 2013 | >0% | L1 (bp5606-7119) | 41 | 12 (2.4/20) | 51.1 (10.7/21) |
| Total N – n/N | 41 | 2.4/20 | 10.7/21 | ||
| HPV 58 LCR | |||||
| Murakami 2013 | >0% | LCR (LCR5′, Prom, Enh) | 41 | 0 (0/20) | 0 (0/21) |
| Total N – n/N | 41 | 0/20 | 0/21 |
ASCUS: abnormal squamous cells of undetermined significance: Bp: base pair; CIN: cervical intraepithelial neoplasia; Enh: enhancer region; HSIL: high-grade squamous intraepithelial lesion; LCR: long control region; LSIL: low-grade squamous intraepithelial lesion; N: total number of samples; N: number of samples methylated; ICC: invasive cervical cancer Prom: promoter region; Q-test: Cochrane Q test.
Proportion of samples methylated at a CpG and/or gene was defined as: N methylated/N methylated + N unmethylated.
Where studies presented results for multiple CpG sites per gene, the mean result for the gene was meta-analysed.