Association of Human Papillomavirus Type 16 Long Control Region Variations with Cervical Cancer in a Han Chinese Population

Abstract

Objective: High-risk human papillomavirus (HPV) E6 and E7 proteins are the major oncoproteins involved in the tumorigenesis of cervical cancer. The long control region (LCR) in HPV plays an important role in regulating the expression of the E6 and E7 oncogenes. In the current study, we investigated the association of HPV16 LCR variations with cervical cancer. Methods: A total of 139 HPV16-positive cervical cancer patients (case group) and 116 HPV16-positive asymptomatic individuals (control group) were enrolled in the current study. Then, the HPV16 LCR was sequenced to determine the association between LCR variations and cervical cancer.Results: In the current study, HPV16 A1-A3 (19.4%), A4 (78.4%) and D3 (2.2%) variants were found in the case group. However, only A1-A3 (34.5%) and A4 variants (65.5%) were found in the control group. The distribution of the HPV16 variants between the case and control groups was significantly different (P=0.009). Moreover, a total of eleven variations (A7167G, A7173C, C7176T, C7200T, T7269C, C7286A, C7729A, C7763T, A7841G, G7867A and T24C) were significantly different between the case and control groups (P<0.05). For the sub-lineage analysis, only C7873G variations were significantly different between the case and control groups in the A4 (As) variant (P=0.039). Conclusion: Our results showed that specific variations in the HPV16 LCR were associated with cervical cancer. Our study will provide a good reference for further understanding of the relationship between HPV16 LCR variation and cervical cancer.

Genetic variation within the human papillomavirus type 16 genome is associated with oropharyngeal cancer prognosis

“…Variation in the URR region near position 7173 has been previously reported in several studies of cervical cancer. 30,[53][54][55] This region of the URR is postulated to contain multiple binding sites for C/EBPβ 30 and FOXA1. 55 Both C/EBPβ and FOXA1 are transcription factors with important roles in tumorigenesis, [55][56][57][58][59][60][61] and have been shown to regulate HPV16 transcription.…”

Genetic variations in the long control region of human papillomavirus type 16 isolates from India: implications for cervical carcinogenesis

“…The variations T6586C, G6657A and T6850G were identified to be significantly associated with high-grade cervical disease status and could serve as molecular markers of the disease status subject to further validation. Previous studies have also reported the association of LCR variations and cervical disease status [4, 9, 16, 30–33].…”

“…The HPV16 genome is divided into three domains, namely, the early region encoding the E1, E2, E4, E5, E6 and E7 genes; the late region encoding the L1 and L2 genes; and the non-coding long control region (LCR) [2][3][4]. The LCR is located between the L1 and E6 genes and comprises approximately 10 % of the viral genome.…”

“…It contains regulatory elements for viral transcription and replication. The LCR is divided into three distinct segments, namely, the 5′ segment (~300 bp), which contains the first two E2-binding sites along with the transcription termination and polyadenylation site; the central segment (~400 bp), which functions as an epithelial-specific transcriptional enhancer and harbours motifs that are essential for viral transcriptional activity; and the 3′ segment (~140 bp), which contains the other two E2-binding sites in addition to the E1-binding site, which overlaps the origin of replication [4][5][6]. Cervical carcinogenesis is induced through dysregulation of E6 and E7 oncogene expression, which in turn is controlled by the p97 promoter located in the E6 proximal part of LCR [7].…”

Genetic variability of the HPV16 early genes and LCR. Present and future perspectives

“…Nowadays, the sequence analysis of LCR is widely used for the classification of HPV16 DNA into the four major phylogenetic branches (Refs [135][136][137][138][139][140]. Specific intratypic nucleotide polymorphisms have been associated with A4 sub-lineage (A7729C and G7841A), B lineage (G7488A, C7688A, C7763T, C7785T and G7833T), C lineage (A7484C, C7488A, C7668T, C7688A, C7763T, C7785T, G7825A, G7833T, A7836C and G7838G) and D lineage (A7484C, G7488A, C7668T, C7688A, A7728T, T7742G, C7763T and C7785T) (Ref.…”