Table 1.

Published studies of human papillomavirus DNA methylation

First author (y)MethodSpecimen typeSample size (cases/controls)OutcomesLocation 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 sequencingExfoliated cervical cells and FFPE biopsy samples56/25NILM, CIN1–CIN3, SCCURR (11)
Hublarova (2009)MS-restriction digestionExfoliated cervical cells and fresh frozen biopsies120/218NILM, CIN1-CIN3, ICCURR (6)
Piyathilake (2011)PyrosequencingExfoliated cervical cells30/45≤CIN1, CIN2+URR (6)
Xi (2011)Bisulfite sequencingExfoliated cervical cells94/117<CIN2/3, CIN2/3URR (11)
Mazumder (2011)MS-restriction digestionFresh frozen biopsies205/34CIN1–CIN3, ICCURR (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 sequencingExfoliated cervical cells and fresh frozen biopsies57/15NILM, SCCURR (11)
Hong (2008)PyrosequencingExfoliated cervical cells14/56NILM, CIN1–CIN3, ICCURR (8)
Ding (2009)Bisulfite sequencingCervical scrapes/biopsy tissues36/17LSIL, HSIL, SCCURR (15)
Vinokurova & von Knebel Doeberitz (2011)LCM, bisulfite sequencing, COBRAFFPE tissue sections40/3NILM, LSIL, HSILURR (16)
Snellenberg (2011)Methylation independent PCR, luminex xMapFFPE biopsy samples, exfoliated cervical cells48/17NILM, CIN3, SCCE2 binding sites, URR (3)
Methylation of L1 is associated with high-grade lesions and cancer
Kalantari (2004)Bisulfite sequencingNot specified64/51NILM, CIN1–CIN3, ICC3′ L1 – URR (19)
Brandsma (2009)Bisulfite sequencingCervical cells (PreservCyt)9/4NILM, ASC-US, LSIL, CIN1–CIN3Genome (113)
Fernandez (2009)Bisulfite sequencing and MSPNot specified70/17NILM, CIN1–CIN3, SCCGenome (110; BS.) L2/L1 (BS; MSP)
Kalantari (2009)LCM, bisulfite sequencingFFPE biopsy samples5/2NILM, ICC3′ end of L1 – URR (19)
Kalantari (2010)Bisulfite sequencingExfoliated cervical cells21/0LSIL, HSIL3′ L1 (4)
Sun (2011)Epityper and pyrosequencingExfoliated cervical cells39/46NILM, LSIL/CIN1, CIN2/3, ICCL1 – URR (32)
Mirabello (2012)PyrosequencingExfoliated cervical cells65/34Cleared HPV, persistent HPV, CIN3Genome (67)
Mirabello (2012)PyrosequencingExfoliated cervical cells181/95Cleared HPV, persistent HPV, CIN2+Genome (66)
Methylation of other HPV types is associated with high-grade lesions and cancer
Badal (2004)Bisulfite sequencingNot specified6/5NILM, ICCL1 – URR (39)
Turan (2006)Bisulfite sequencingCervical smears/tumor biopsies13/11NILM, ASC-US, LSIL, HSIL, SCCL1 – URR (31)
Fernandez (2009)Bisulfite sequencing, MSP for E2Not specified29/10NILM, CIN1–3, SCCGenome (168)
Wentzensen (2012)PyrosequencingExfoliated cervical cellsHPV18: 40/42<CIN2/ASCUS, CIN3Genome (106)
HPV31: 45/43<CIN2/ASCUS, CIN3Genome (80)
HPV45: 12/11<CIN2/ASCUS, CIN3Genome (105)

Abbreviations: ASC-US, atypical squamous cells of undetermined significance; BS, bisulfite sequencing; FFPE, formalin-fixed, paraffin-embedded; ICC, invasive cervical cancer; LCM, laser-capture microdissection; MS, methylation sensitive; NILM, negative for intraepithelial lesion or malignancy.