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

Abstract

Human papillomavirus 16 (HPV16) infection is the aetiologic factor for the development of cervical dysplasia and is regarded as highly carcinogen, because it is implicated in more than 50% of cervical cancer cases, worldwide. The tumourigenic potential of HPV16 has triggered the extensive sequence analysis of viral genome in order to identify nucleotide variations and amino acid substitutions that influence viral oncogenicity and subsequently the initiation and progression of cervical cancer. Nowadays, specific mutations of HPV16 DNA have been associated with an increased risk of high-grade squamous intraepithelial lesions and invasive cervical cancer (ICC) development, including E6 : Q14H, H78Y, L83V, Ε7 : N29S, S63F, E2 : H35Q, P219S, T310K, E5 : I65V, whereas highly conserved regions of viral DNA have been extensively characterised. In addition, numerous novel HPV16 mutations are observed among the studied populations from various geographic regions, hence advocating that different HPV16 strains seem to emerge with different tumourigenic capacities. The present review focuses on the variability of the early genes and the long control region, emphasising on the association of specific mutations with the development of severe dysplasia. Finally, it evaluates whether specific regions of HPV16 DNA are able to serve as valuable biomarkers for cervical cancer risk.

Phylogenetic analysis and antigenic epitope prediction for E6 and E7 of Alpha-papillomavirus 9 in Taizhou, China

“…No positive selection sites for HPV52 E6 and E7 genes have been reported in central and Southwest China [ 38 , 39 ]. In addition, selective pressure analysis from non-Asian population showed different results, with 10R, 14H, 83V in HPV E6 and 85G in HPV16 E7 under positive selective pressure [ 40 , 41 ]. Therefore, these results indicate that genetic variations among HPV types may lead to biological advantages through fixed mutations in their genomes and that even small variations might lead to minor adaptive improvements.…”

Genetic diversity of E6, E7 and the long control region in human papillomavirus type 16 variants in Beijing, China

“…The LCR contains the early promoter and various transcriptional regulatory sites of involved in viral DNA replication and transcription [ 32 , 33 ], such as E2, YY1, NF1, FOS, NFKB1, and others. Several studies have suggested that certain LCR variants of HPV16 may play an important role in viral persistence and the development of cervical cancer [ [34] , [35] , [36] ]. For example, Dong et al suggested that the mutation of the LCR sequence of HPV16-positive cervical cancer patients is mainly located in the YY1 binding region [ 37 , 38 ].…”

High-Risk Human Papillomavirus Infection in Lung Cancer: Mechanisms and Perspectives

“…Cellular transcription factors including Ying-yang 1(YY1), Nuclear-factor 1(NF1), Activator protein 1 (AP1), Glucocorticoid receptor (GR) and Progesterone receptor (PR), among others, can bind to the cognate site in this region for viral gene expression regulation. Additionally, viral E2 protein binding to cognate sites inside the LCR stimulate or to suppress the viral transcriptional activity with effects depending on different HPV types and variants [ 19 , 20 , 21 ]. The E region encodes all the non-structural E1, E2, E4, E5, E6 and E7 proteins, with them having major functions in viral replication and cell transformation [ 22 ].…”