Patterns of cellular and HPV 16 methylation as biomarkers for cervical neoplasia.
Aberrant promoter methylation of biologically relevant genes in cervical cancer and uneven CpG distribution within the human papillomavirus 16 (HPV 16) enhancer region have been reported. Cervical samples and questionnaires from 151 women screened for cervical cancer in Appalachian Ohio were analyzed. Methylation was measured by bisulfite sequencing in candidate gene sites in ESR1, DCC, p16, and LINE1 elements. Among 89 HPV 16-positive women, CpG sites in the E6 promoter and enhancer regions and the L1 region of the HPV 16 genome were measured. Methylation levels were compared by cervical cytology and HPV 16 status. HPV methylation was low regardless of cytology status, however E6 methylation was significantly higher in women with normal cytology. ESR1 and DCC methylation were significantly higher in HPV 16-positive women. Increased methylation at sites in the E6 promoter region was associated with lower odds of abnormal cytology. Increased methylation in candidate genes was associated with higher odds of abnormal cytology, particularly DCC region 2.4, DCC region 2.6, ESR1 region 3.2, and LINE1 site 1.2. HPV 16 genome CpG methylation was low except for the L1 region. In general, lower HPV 16 methylation and higher candidate gene methylation levels were associated with higher odds of abnormal cytology.
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University, FMB 307, 330 Cedar Street, New Haven, CT 06520, USA. divya.patel@yale.edu
Divya A
DA
Patel
Laura S
LS
Rozek
Justin A
JA
Colacino
Adrienne
A
Van Zomeren-Dohm
Mack T
MT
Ruffin
Elizabeth R
ER
Unger
Dana C
DC
Dolinoy
David C
DC
Swan
Juanita
J
Onyekwuluje
Cecilia R
CR
DeGraffinreid
Electra D
ED
Paskett
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D003584:Cytological Techniques / Q000379:methods*; D019175:DNA Methylation; D004279:DNA, Viral / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D052162:Human papillomavirus 16 / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009820:Ohio; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis* / Q000821:virology*; D014773:Virology / Q000379:methods*; D055815:Young Adult
D014408:Biomarkers, Tumor; D004279:DNA, Viral