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

Authors

Jennifer M Geris
E Susan Amirian
Deborah A Marquez-Do
Martial Guillaud
Laura M Dillon
Michele Follen
Michael E Scheurer

Publication Date

8-1-2023

Journal

Cancer Prevention Research

DOI

10.1158/1940-6207.CAPR-23-0051

PMID

37217238

PMCID

PMC10524768

PubMedCentral® Posted Date

2-1-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Female, Humans, Uterine Cervical Neoplasms, DNA End-Joining Repair, Human Papillomavirus Viruses, Papillomavirus Infections, Uterine Cervical Dysplasia, Human papillomavirus 16, DNA, Viral, Papillomaviridae, Human Papillomavirus, Integration, Cervical Dysplasia, DNA repair, Non-Homologous End-Joining

Abstract

Previous evidence indicates that 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 single nucleotide polymorphisms (SNPs) in non-homologous 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 HSIL, 251 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.