Genetic variability and functional implication of HPV16 from cervical intraepithelial neoplasia in Shanghai women

Abstract

Human papillomavirus (HPV)16 gene mutation is usually associated with persistent HPV infection and cervical intraepithelial neoplasia (CIN). However, the functional implications of HPV16 mutations remain poorly understood.145 LCR/E6/E7 of the HPV16 isolates were amplified and sequenced, and HPV16 integration status was detected. In total, 89 SNPs (68 in the LCR, 13 in E6, 8 in E7) were discovered, 11 of which were nonsynonymous mutations (8 in E6, 3 in E7). The H85Y and E120D variants in E6 were significantly reduced in the high-grade squamous intraepithelial lesion (HSIL) group compared to the <HSIL group (P = .046 and .005), conversely the N29S in E7(P = .01). Amino acid substitutions (D32N/E, E36Q, H85Y, and E120D in E6 and N29H/S and R77C in E7) were predicted to have an effect on conserved structural and functional residues, and five amino acid substitutions (H85Y, E36Q, I34L, and D32E in E6; R77C in E7) would potentially change the secondary structure. "6329G>T," a potential binding site for TATA-binding protein, is the most common in LCR variants. A4 (Asian) was associated with an increased risk of HSIL compared to A1-3(P = .009). The H85/E120 in E6 and N29 in HPV16 E7 might play a critical role in carcinogenesis by disrupting p53 and Rb degradation due to affecting their interaction, respectively. In a word, the findings in this study provide preventative and therapeutic interventions of HPV16 -related cervical lesions/cancer.

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

“…The viral E2 protein is known to bind as a dimer to the LCR recognition sites and regulate the expression of E6 and E7 genes [41], and variation G7004A/C might impact the binding efficiency of the viral E2 protein to the LCR. It is noteworthy that none of our samples showed variations in the YY1 binding site that are reported to impact the overexpression of viral oncogenes and tumour progression [16,20,33,42]. Similarly, previous studies have also reported variations in viral and cellular TFbs in HPV16 LCR from Europe, Thailand, and PR China [9,16,31,33,43,44].…”

“…It is noteworthy that none of our samples showed variations in the YY1 binding site that are reported to impact the overexpression of viral oncogenes and tumour progression [16,20,33,42]. Similarly, previous studies have also reported variations in viral and cellular TFbs in HPV16 LCR from Europe, Thailand, and PR China [9,16,31,33,43,44]. Several single and cooccurring variations have been characterized in Indian isolates of HPV16 and their correlation with disease grade status has been studied.…”

“…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].…”

Epidemiology and Molecular Biology of HPV Variants in Cervical Cancer: The State of the Art in Mexico

“…Many HPV intratype variants have been isolated in various clinical studies and a careful classification of variants of the most frequent HPV types in cancer has been achieved [ 9 , 15 , 17 ]. It has been postulated that nucleotide variations that occur among HPV intratype variants are reflected in functional differences and in their pathogenicity [ 18 , 19 , 20 , 21 ]. Currently, there are many studies that report that HPV-16 and -18 intratype variants differentially alter host cells, which translates into different risks of persistence and progression to cancer [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ].…”

Cervical Neoplasia: Papillomavirus Infection and Resistance to Anti Tumor Immunity

“…Several other authors show that the biomarkers Ki67 and TP53 are also considered to be a marker of high oncogenic Papillomavirus infection in intraepithelial neoplasia of the cervix [21][22][23]. Further research is focusing on identification of viral oncopreteins E6 and E7 as markers of high-risk Papillomavirus infection in intraepithelial neoplasia [24][25][26]. PD-L1 is involved in the molecular mechanism of cervical carcinogenesis by resistance to anti-tumor immunity of intraepithelial neoplasia cells [27,28].…”