Abstract
The present study investigated the association between single nucleotide polymorphisms (SNPs) in immune- or DNA repair-related genes and the integration pattern of human papillomavirus (HPV), a promising prognostic marker in cervical cancer. The HPV integration patterns of cervical cancer patients were determined by polymerase chain reaction and in situ hybridization, and categorized as episomal (group A), single-copy or multi-copy tandem repetition integrated (group B), and undetectable HPV types (group C). After sample and SNP quality control, 166,505 SNPs in 161 samples (38, 111, and 12 patients in groups A, B, and C, respectively) were examined. None of the SNPs reached genome-wide significance, and several candidate SNPs for future study were selected, including rs10999435 on chromosome 10q22, rs1322054 on chromosome 9q32-33, and rs10902171 on chromosome 11p15. Luciferase assay identified rs1322054 as the primary functional variant to regulate gene expression in immune cell. Further studies are needed to determine the genetic background of different integration patterns of HPV in cervical cancer patients.
Highlights
Current standard treatment for patients with locally advanced cervical cancer is radiotherapy with concurrent chemotherapy
We report the first comprehensive association study to identify single nucleotide polymorphisms (SNPs) on immune- or DNA repair-related genes associated with the integration patterns of human papillomavirus (HPV) in cervical cancer patients
Several genome-wide association studies (GWASs) of cervical cancer development or HPV seropositivity have been reported[19,20], the present study is the first to identify host genetic factors that can affect the integration of HPV DNA
Summary
Current standard treatment for patients with locally advanced cervical cancer is radiotherapy with concurrent chemotherapy. High-risk HPV develops several mechanisms to avoid host immune response and persists as episomes in the HPV-infected cells in transformation zone of the cervix before progression to cervical cancer. The persistence of episomal HPV DNA in transformed cells provides high amounts of viral antigen through active replication, E2 These cells are preferentially targeted by the immune system[5] compared with cells with no or lower rates of viral replication. We showed that genetic variants of excision base repair proficiency genes are strongly associated with cervical cancer compared with the healthy control population This finding suggests that an individual host’s base excision repair or nucleotide excision repair ability may facilitate HPV viral persistence and cervical carcinogenesis[9]. We hypothesized that genomic susceptibility to DNA damage may explain the association between differential HPV integration and radiotherapy outcome in cervical cancer patients. We investigated the potential relationship between genomic variants of DNA damage repair- and immune-related genes and different HPV integration patterns using a customized single nucleotide polymorphism (SNP) array system
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