April 6, 2018
A new study co-authored by researchers in the University of North Carolina at Chapel Hill’s Gillings School of Global Public Health is among the first to assess DNA methylation of imprinted genes as a potential biomarker for the progression of cervical dysplasia.
DNA methylation is the process by which methyl groups – made up of carbon and hydrogen atoms – are added to a DNA molecule, changing the activity of a DNA segment and affecting gene expression. In relationship to cervical cancer, differential methylation patterns may help to predict the risk of high-grade cervical intraepithelial neoplasia (CIN), a severe precancerous condition involving abnormal cell growth on the cervix.
The full study that yielded these findings, titled “DNA methylation of imprinted gene control regions in the regression of low-grade cervical lesions,” was published online February 28 by the International Journal of Cancer.
Study co-authors associated with the Gillings School include primary author Ayodele Gomih, PhD, a 2017 alumna who currently is a postdoctoral research associate at the University of Miami’s Miller School of Medicine; Kari E. North, PhD, professor of epidemiology; Michael G. Hudgens, PhD, professor of biostatistics; Jennifer S. Smith, PhD, professor of epidemiology; and Wendy R. Brewster, MD, PhD, adjunct professor of epidemiology, professor of gynecologic oncology and director of the UNC Center for Women’s Health Research. Smith and Brewster both are members of UNC’s Lineberger Comprehensive Cancer Center.
To conduct the CIN Cohort Study (led by study co-authors Catherine Hoyo, PhD, and Susan K. Murphy, PhD), researchers recruited 164 patients with CIN from 10 Duke University clinics. Most participants (80.5 percent) tested positive for infection with human papillomavirus (HPV) at the time of study enrollment. Participants had colposcopies at enrollment and participated in up to five follow-up visits over three years. Using DNA extracted from exfoliated cervical cells, the researchers conducted methylation quantitation and HPV genotyping.
Their analysis revealed that among women with CIN, increased methylation at regulatory regions of the genes IGF2 and Kv was less likely to regress to normal cervical histology compared to regions with lower methylation. These imprinted gene regions, previously implicated in breast, colorectal and other cancers, may be possible targets for assessing the risk of cervical dysplasia progression.
“A major advantage of this study was the ability to prospectively assess the association between methylation markers and CIN,” the study authors wrote.
“In the context of high-risk HPV – the primary cause of invasive cervical cancer – which currently is used for cancer screening, differential methylation patterns may be reflective of responses to persistent HPV infection or other environmental factors that influence host epigenetic responses,” Gomih added. “Defining specific methylation patterns can help characterize higher-risk cases, further supporting the consideration of imprinted gene biomarkers as a screening tool for cervical dysplasia.”
Considering the evidence that altered methylation may play a role in the natural history of CIN, the co-authors proposed larger research studies in the future. These should include an assessment of gene expression changes, they wrote, to confirm the association and determine the efficacy of imprinted gene DMR methylation as a biomarker with the potential to improve cervical cancer screening and early detection.
Other study co-authors included Zhiqing Huang, MD, PhD, David Skaar, PhD, Fidel Valea, MD, Rex C. Bentley, MD, Adriana C. Vidal, PhD, Rachel L. Maguire, MPH, and Randy L. Jirtle, PhD.