Michael E. Scheurer

Polymorphisms in the Nonhomologous End-joining DNA Repair Pathway are Associated with HPV Integration in Cervical Dysplasia

Abstract Previous evidence indicates that human papillomavirus (HPV) integration status may be associated with cervical cancer development and progression. However, host genetic variation within genes that may play important roles in the viral integration process is understudied. The aim of this study was to examine the association between HPV16 and HPV18 viral integration status and SNPs in nonhomologous-end-joining (NHEJ) DNA repair pathway genes on cervical dysplasia. Women enrolled in two large trials of optical technologies for cervical cancer detection and positive for HPV16 or HPV18 were selected for HPV integration analysis and genotyping. Associations between SNPs and cytology (normal, low-grade, or high-grade lesions) were evaluated. Among women with cervical dysplasia, polytomous logistic regression models were used to evaluate the effect of each SNP on viral integration status. Of the 710 women evaluated [149 high-grade squamous intraepithelial lesion (HSIL), 251; low-grade squamous intraepithelial lesion (LSIL, 310 normal)], 395 (55.6%) were positive for HPV16 and 192 (27%) were positive for HPV18. Tag-SNPs in 13 DNA repair genes, including RAD50, WRN, and XRCC4, were significantly associated with cervical dysplasia. HPV16 integration status was differential across cervical cytology, but overall, most participants had a mix of both episomal and integrated HPV16. Four tag-SNPs in the XRCC4 gene were found to be significantly associated with HPV16 integration status. Our findings indicate that host genetic variation in NHEJ DNA repair pathway genes, specifically XRCC4, are significantly associated with HPV integration, and that these genes may play an important role in determining cervical cancer development and progression. Prevention Relevance: HPV integration in premalignant lesions and is thought to be an important driver of carcinogenesis. However, it is unclear what factors promote integration. The use of targeted genotyping among women presenting with cervical dysplasia has the potential to be an effective tool in assessing the likelihood of progression to cancer.

Self-Sampling for Human Papillomavirus Testing: Acceptability in a U.S. Safety Net Health System

Self-sampling for human papillomavirus testing is increasingly recognized as a strategy to expand cervical cancer screening access and utilization. Acceptability is a key determinant of uptake. This study assesses the acceptability of and experiences with mailed self-sampling kits for human papillomavirus testing among underscreened patients in a safety net health system. A nested telephone survey was administered between 2021 and 2023 to a sample (n=272) of the 2,268 participants enrolled in the Prospective Evaluation of Self-Testing to Increase Screening trial. Trial participants include patients of a safety net health system aged 30-65 years who were not up to date on screening. Participants were asked about barriers to provider-performed screening. Kit users and nonusers were asked about their experiences. Prevalent barriers to provider-performed screening included perceived discomfort of pelvic examination (69.4%), being uncomfortable with male providers (65.4%), and embarrassment (57.0%). Among participants who reported using the mailed kit (n=164), most reported good experiences (84.8%). Most reported self-sampling as more/equally convenient (89.0%), less/equally embarrassing (99.4%), and less/equally stressful (95.7%) than provider-performed screening. Among kit nonusers (n=43), reasons for not using the kit included forgetting about it (76.7%), preferring provider-performed screening (76.7%), and fearing cancer (67.4%). Prospective Evaluation of Self-Testing to Increase Screening trial participants generally had a positive experience with self-sampling for human papillomavirus testing. Increased comfort and reduced embarrassment/anxiety with self-sampling are relevant attributes because these were the most prevalent reported barriers to provider-performed screening. High acceptability suggests potentially high uptake when self-sampling for human papillomavirus testing receives regulatory approval and is available in safety net health systems.