|
1
|
da Silva-Júnior AHP, de Oliveira Silva RC, Gurgel APAD, Barros-Júnior MR, Nascimento KCG, Santos DL, Pena LJ, Lima RDCP, Batista MVDA, Chagas BS, de Freitas AC. Identification and Functional Implications of the E5 Oncogene Polymorphisms of Human Papillomavirus Type 16. Trop Med Infect Dis 2024; 9:140. [PMID: 39058182 PMCID: PMC11281449 DOI: 10.3390/tropicalmed9070140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 06/12/2024] [Accepted: 06/21/2024] [Indexed: 07/28/2024] Open
Abstract
The persistence of the human papillomavirus type 16 (HPV16) infection on the cervical epithelium contributes to the progression of cervical cancer. Studies have demonstrated that HPV16 genetic variants may be associated with different risks of developing cervical cancer. However, the E5 oncoprotein of HPV16, which is related to several cellular mechanisms in the initial phases of the infection and thus contributes to carcinogenesis, is still little studied. Here we investigate the HPV16 E5 oncogene variants to assess the effects of different mutations on the biological function of the E5 protein. We detected and analyzed the HPV16 E5 oncogene polymorphisms and their phylogenetic relationships. After that, we proposed a tertiary structure analysis of the protein variants, preferential codon usage, and functional activity of the HPV16 E5 protein. Intra-type variants were grouped in the lineages A and D using in silico analysis. The mutations in E5 were located in the T-cell epitopes region. We therefore analyzed the interference of the HPV16 E5 protein in the NF-kB pathway. Our results showed that the variants HPV16E5_49PE and HPV16E5_85PE did not increase the potential of the pathway activation capacity. This study provides additional knowledge about the mechanisms of dispersion of the HPV16 E5 variants, providing evidence that these variants may be relevant to the modulation of the NF-κB signaling pathway.
Collapse
Affiliation(s)
- Antônio Humberto P. da Silva-Júnior
- Laboratory of Molecular Studies and Experimental Therapy (LEMTE), Department of Genetics, Federal University of Pernambuco, Recife 50670-901, Pernambuco, Brazil; (A.H.P.d.S.-J.); (R.C.d.O.S.); (M.R.B.-J.); (K.C.G.N.); (D.L.S.); (R.d.C.P.L.); (B.S.C.)
| | - Ruany Cristyne de Oliveira Silva
- Laboratory of Molecular Studies and Experimental Therapy (LEMTE), Department of Genetics, Federal University of Pernambuco, Recife 50670-901, Pernambuco, Brazil; (A.H.P.d.S.-J.); (R.C.d.O.S.); (M.R.B.-J.); (K.C.G.N.); (D.L.S.); (R.d.C.P.L.); (B.S.C.)
| | - Ana Pavla A. Diniz Gurgel
- Department of Engineering and Environment, Federal University of Paraiba, João Pessoa 58033-455, Paraíba, Brazil;
| | - Marconi Rêgo Barros-Júnior
- Laboratory of Molecular Studies and Experimental Therapy (LEMTE), Department of Genetics, Federal University of Pernambuco, Recife 50670-901, Pernambuco, Brazil; (A.H.P.d.S.-J.); (R.C.d.O.S.); (M.R.B.-J.); (K.C.G.N.); (D.L.S.); (R.d.C.P.L.); (B.S.C.)
| | - Kamylla Conceição Gomes Nascimento
- Laboratory of Molecular Studies and Experimental Therapy (LEMTE), Department of Genetics, Federal University of Pernambuco, Recife 50670-901, Pernambuco, Brazil; (A.H.P.d.S.-J.); (R.C.d.O.S.); (M.R.B.-J.); (K.C.G.N.); (D.L.S.); (R.d.C.P.L.); (B.S.C.)
| | - Daffany Luana Santos
- Laboratory of Molecular Studies and Experimental Therapy (LEMTE), Department of Genetics, Federal University of Pernambuco, Recife 50670-901, Pernambuco, Brazil; (A.H.P.d.S.-J.); (R.C.d.O.S.); (M.R.B.-J.); (K.C.G.N.); (D.L.S.); (R.d.C.P.L.); (B.S.C.)
| | - Lindomar J. Pena
- Laboratory of Virology and Experimental Therapy, Instituto Aggeu Magalhães (IAM), Oswaldo Cruz Foundation, Recife 50670-901, Pernambuco, Brazil;
| | - Rita de Cássia Pereira Lima
- Laboratory of Molecular Studies and Experimental Therapy (LEMTE), Department of Genetics, Federal University of Pernambuco, Recife 50670-901, Pernambuco, Brazil; (A.H.P.d.S.-J.); (R.C.d.O.S.); (M.R.B.-J.); (K.C.G.N.); (D.L.S.); (R.d.C.P.L.); (B.S.C.)
| | - Marcus Vinicius de Aragão Batista
- Laboratory of Molecular Genetics and Biotechnology (GMBio), Department of Biology, Federal University of Sergipe, São Cristóvão 49107-230, Sergipe, Brazil
| | - Bárbara Simas Chagas
- Laboratory of Molecular Studies and Experimental Therapy (LEMTE), Department of Genetics, Federal University of Pernambuco, Recife 50670-901, Pernambuco, Brazil; (A.H.P.d.S.-J.); (R.C.d.O.S.); (M.R.B.-J.); (K.C.G.N.); (D.L.S.); (R.d.C.P.L.); (B.S.C.)
| | - Antonio Carlos de Freitas
- Laboratory of Molecular Studies and Experimental Therapy (LEMTE), Department of Genetics, Federal University of Pernambuco, Recife 50670-901, Pernambuco, Brazil; (A.H.P.d.S.-J.); (R.C.d.O.S.); (M.R.B.-J.); (K.C.G.N.); (D.L.S.); (R.d.C.P.L.); (B.S.C.)
| |
Collapse
|
|
2
|
Worku E, Yigizaw G, Admassu R, Mekonnen D, Gessessa W, Tessema Z, Walle T. Prevalence and risk factors associated with precancerous and cancerous cervical lesions among HIV-infected women in University of Gondar specialized comprehensive referral hospital, Northwest Ethiopia: cross-sectional study design. BMC Womens Health 2024; 24:322. [PMID: 38834999 DOI: 10.1186/s12905-024-03174-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 05/29/2024] [Indexed: 06/06/2024] Open
Abstract
BACKGROUND Cervical cancer is one of the leading causes of death in women worldwide. The majority of the cases are found in developing countries. The increasing risk of cervical cancer prevalence and growing danger of death from cervical cancer and the high occurrence of human papillomavirus (HPV) infection in women who are HIV positive give us the ground to study the prevalence and associated risk factors. OBJECTIVE The study aims to assess the prevalence of cervical cancer screening and associated risk factors among HIV-positive women attending the Adult ART clinic at the University of Gondar Hospital. METHODS An institution-based cross-sectional study was conducted from March to August 2021, on adult HIV-positive women attending the Adult ART clinic at Gondar University Referral Hospital by phone calling patients per week for six months to complete a total of 2744 HIV-positive patients who were not screened for cervical cancer before. The data were collected using an interviewer-administered questionnaire. Bivariate and multivariable logistic regression analyses were used to determine the presence and the degree of association between dependent and independent variables. In the multivariable logistic analysis, a P-value of < 0.05 and odds ratio with a 95% confidence interval were considered to determine independent predictors for the prevalence of premalignant or malignant cervical lesions among HIV-positive patients. RESULT This study assessed 915 HIV Positive women who were screened for cervical cancer via visual inspection with acetic acid (VIA) as the primary screening tool and found that 24.48% had positive VIA results. Those with VIA-positive cases pathology examination showed 72.4% had abnormal pathology reports (CIN 1/2/3-51.25%, 17.23% cancer & 3.9% CIS), strengthening the finding in many studies that suggest HIV-positive women have a high rate of premalignant lesions.
Collapse
Affiliation(s)
- Elfalet Worku
- Gynecology oncologist Department of Obstetrics and Gynecology College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Getachew Yigizaw
- Gynecology oncologist Department of Obstetrics and Gynecology College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Robel Admassu
- Gynecology oncologist Department of Obstetrics and Gynecology College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Dawit Mekonnen
- Gynecology oncologist Department of Obstetrics and Gynecology College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Winta Gessessa
- Gynecology oncologist Department of Obstetrics and Gynecology College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Zemenu Tessema
- Departments of Epidemiology and Biostatistics, Institute of Public Health, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Tarkie Walle
- Department of Surgical Nursing, School of Nursing, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia.
| |
Collapse
|
|
3
|
Galati L, Di Bonito P, Marinaro M, Chiantore MV, Gheit T. HPV16 Phylogenetic Variants in Anogenital and Head and Neck Cancers: State of the Art and Perspectives. Viruses 2024; 16:904. [PMID: 38932197 PMCID: PMC11209046 DOI: 10.3390/v16060904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 05/27/2024] [Accepted: 05/29/2024] [Indexed: 06/28/2024] Open
Abstract
HPV16 is responsible for approximately 60% and 90% of global HPV-induced cervical and oropharyngeal cancers, respectively. HPV16 intratype variants have been identified by HPV genome sequencing and classified into four phylogenetic lineages (A-D). Our understanding of HPV16 variants mostly derives from epidemiological studies on cervical cancer (CC) in which HPV16 B, C, and D lineages (previously named "non-European" variants) were mainly associated with high-grade cervical lesions and cancer. Although a predominance of HPV16 lineage A (previously named "European variants") has been observed in head and neck squamous cell carcinoma (HNSCC), epidemiological and in vitro biological studies are still limited for this tumor site. Next Generation Sequencing (NGS) of the entire HPV genome has deepened our knowledge of the prevalence and distribution of HPV variants in CC and HNSCC. Research on cervical cancer has shown that certain HPV16 sublineages, such as D2, D3, A3, and A4, are associated with an increased risk of cervical cancer, and sublineages A4, D2, and D3 are linked to a higher risk of developing adenocarcinomas. Additionally, lineage C and sublineages D2 or D3 of HPV16 show an elevated risk of developing premalignant cervical lesions. However, it is still crucial to conduct large-scale studies on HPV16 variants in different HPV-related tumor sites to deeply evaluate their association with disease development and outcomes. This review discusses the current knowledge and updates on HPV16 phylogenetic variants distribution in HPV-driven anogenital and head and neck cancers.
Collapse
Affiliation(s)
- Luisa Galati
- International Agency for Research on Cancer, 69007 Lyon, France
| | - Paola Di Bonito
- Department of Infectious Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy; (P.D.B.); (M.M.); (M.V.C.)
| | - Mariarosaria Marinaro
- Department of Infectious Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy; (P.D.B.); (M.M.); (M.V.C.)
| | - Maria Vincenza Chiantore
- Department of Infectious Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy; (P.D.B.); (M.M.); (M.V.C.)
| | - Tarik Gheit
- International Agency for Research on Cancer, 69007 Lyon, France
| |
Collapse
|
|
4
|
Zhang L, Li M, Yuan F, Jiang J, Zhang X. The difference of transcriptome of HPV-infected patients contributes more to the occurrence of cervical cancer than the mutations of E6 and E7 genes in HPV16. Medicine (Baltimore) 2024; 103:e36822. [PMID: 38241590 PMCID: PMC10798708 DOI: 10.1097/md.0000000000036822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 12/08/2023] [Indexed: 01/21/2024] Open
Abstract
Human papillomavirus (HPV) E6 and E7 genes are biomarkers and drivers of the progression of cervical cancer (CxCa). The aim of this study was to investigate the relationship between HPV16 E6, E7 gene mutations and the occurrence and development of CxCa. Cervical exfoliated cells and clinical data of patients with cervical diseases were collected. Sample DNA was extracted, the E6 and E7 gene fragments were amplified by PCR, and the mutations were detected by Sanger sequencing and compared with standard sequences. Microarray was used to sequence the transcriptome of cells. Data of transcriptome analyzed and visualized using R software and its packages. Analysis of clinical characteristics demonstrated the association of HPV16 infection with CxCa (P < .05). Sanger sequencing results showed that the mutation sites of E6 gene included T178G/A, T350G, A131C, and T241G; among these, A131C and T241G were synonymous mutations. The mutation sites of E7 gene included A647G, T846C, G666A, T843C, and T760C, and all of them were synonymous mutations except A647G. There was no significant difference in the distribution of HPV16 E6, E7 mutations among CxCa, cervical intraepithelial neoplasia, and infection groups (P > .05). Compared with the non- CxCa group, gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis of differentially expressed genes (DEGs) showed more significant enrichment of DEGs in the biological processes, pathways, and diseases closely related to cancer. Compared with the non-mutation group, the DEGs in the E6, E7 gene mutation group were significantly enriched in the events related to infection and immunity. To summarize, HPV16 may be associated with the occurrence and development of CxCa, but HPV16 E6 and E7 gene mutations have little effect on the occurrence and development of CxCa. Individual differences may have a greater effect on the progression of CxCa.
Collapse
Affiliation(s)
- Lihui Zhang
- Department of Gynaecology, The Second Norman Bethune Hospital of Jilin University, Changchun, China
| | - Mengyuan Li
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, China
| | - Feiyan Yuan
- Department of Gynaecology, The Second Norman Bethune Hospital of Jilin University, Changchun, China
| | - Jingyuan Jiang
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, China
| | - Xinmin Zhang
- Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, China
| |
Collapse
|
|
5
|
Minhas S, Kashif M, Nisar H, Idrees M, Ansari F. Whole-genome analysis and evolutionary characterization of cervical and oral human papillomavirus 16. Exp Biol Med (Maywood) 2023; 248:2332-2340. [PMID: 38196081 PMCID: PMC10903243 DOI: 10.1177/15353702231211861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 08/24/2023] [Indexed: 01/11/2024] Open
Abstract
High-throughput genome-wide sequencing has revealed high genomic variability of HPV16 in different geographic regions which is the most predominant genotype in human papillomavirus (HPV)-associated malignancies. Analysis of the HPV16 by whole-genome sequence (WGS) is an advanced method for the identification of mutations in the genome. There is limited information about HPV16 diversity in Pakistan, especially at the genomic level. Till now, WGS for HPV16 has not been previously reported in Pakistan. The current study has sequenced three HPV16 viral genomes, from two cervical and one oral cavity positive sample of women presented with general gynecological problems without any evidence of precancerous or cancerous lesions using an ion ampliseq customized panel. Sequencing analysis detected 38 variations, including single-nucleotide polymorphisms (SNPs) and two Indels, across three samples with the highest number of SNPs present in E1, E2, and L2, respectively. A total of 20 non-synonymous and 11 synonymous mutations with amino acid substitutions (T1421C, G1515A, T2223C, T1389C, G1483A, and T2191C) were identified. The phylogenetic analysis revealed the genomes of HPV16 are closely associated with those reported from Thailand and the United States. These are the first HPV16 WGS from Pakistan. However, more research is needed with a large sample size from diversified areas to assess the carcinogenic consequences and impact of HPV vaccinations.
Collapse
Affiliation(s)
- Sadia Minhas
- Department of Microbiology, Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore 54000, Pakistan
- Department of Oral Pathology, Akhtar Saeed Medical & Dental College Lahore, Lahore 54000, Pakistan
| | - Muhammad Kashif
- Department of Oral Pathology, Bakhtawar Amin Medical & Dental College, Multan 60000, Pakistan
| | - Haseeb Nisar
- Department of Life Sciences, University of Management and Technology, Lahore 54000, Pakistan
| | - Muhammad Idrees
- Center of Excellence in Molecular Biology, The University of Punjab, Lahore 54000, Pakistan
| | - Farheen Ansari
- Department of Microbiology, Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore 54000, Pakistan
| |
Collapse
|
|
6
|
Ye M, Li S, Luo P, Tang X, Gong Q, Mei B. Genetic variation of E6, E7 and L1 genes of human papillomavirus 51 from Central China. J Med Virol 2022; 94:2811-2823. [PMID: 35048388 DOI: 10.1002/jmv.27603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 01/15/2022] [Accepted: 01/17/2022] [Indexed: 11/09/2022]
Affiliation(s)
- Mengxia Ye
- Department of Laboratory MedicineJingzhou Hospital, Yangtze UniversityJingzhouChina
| | - Shuo Li
- Department of Laboratory MedicineJingzhou Hospital, Yangtze UniversityJingzhouChina
| | - Ping Luo
- Department of Laboratory MedicineJingzhou Hospital, Yangtze UniversityJingzhouChina
| | - Xuan Tang
- Department of Laboratory MedicineJingzhou Hospital, Yangtze UniversityJingzhouChina
| | - Quan Gong
- Department of ImmunologySchool of MedicineYangtze UniversityJingzhouChina
| | - Bing Mei
- Department of Laboratory MedicineJingzhou Hospital, Yangtze UniversityJingzhouChina
| |
Collapse
|
|
7
|
Dai MZ, Qiu Y, Di XH, Shi WW, Xu HH. Association of cervical carcinogenesis risk with HPV16 E6 and E7 variants in the Taizhou area, China. BMC Cancer 2021; 21:769. [PMID: 34217247 PMCID: PMC8254333 DOI: 10.1186/s12885-021-08531-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 06/23/2021] [Indexed: 01/17/2023] Open
Abstract
Background Human papillomavirus (HPV) type 16 accounts for a larger share of cervical cancer and has been a major health problem worldwide for decades. The progression of initial infection to cervical cancer has been linked to viral sequence properties; however, the role of HPV16 variants in the risk of cervical carcinogenesis, especially with longitudinal follow-up, is not fully understood in China. Methods We aimed to investigate the genetic variability of HPV16 E6 and E7 oncogenes in isolates from cervical exfoliated cells. Between December 2012 and December 2014, a total of 310 single HPV16-positive samples were selected from women living in the Taizhou area, China. Sequences of all E6 and E7 oncogenes were analysed by PCR-sequencing assay. Detailed sequence comparison, genetic heterogeneity analyses and maximum-likelihood phylogenetic tree construction were performed with BioEdit Sequence Alignment Editor and MEGA X software. Data for cytology tests and histological diagnoses were obtained from our Taizhou Area Study with longitudinal follow-up for at least 5 years. The relationship between HPV16 variants and cervical carcinogenesis risk was analysed by the chi-square test or Fisher’s exact test. Results In this study, we obtained 64 distinct variation patterns with the accession GenBank numbers MT681266-MT681329. Phylogenetic analysis revealed that 98.3% of HPV16 variants belong to lineage A, in which the A4 (Asian) sublineage was dominant (64.8%), followed by A2 (12.1%), A1 (11.4%), and A3 (10.0%). The A4 (Asian) sublineage had a higher risk of CIN2+ than the A1–3 (European) sublineages (OR = 2.69, 95% CI = 1.04–6.97, P < 0.05). Furthermore, nucleotide variation in HPV16 E6 T178G is associated with the development of cervical cancer. Conclusion These data could provide novel insights into the role of HPV16 variants in cervical carcinogenesis risk in China. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08531-y.
Collapse
Affiliation(s)
- Mei-Zhen Dai
- Medical Research Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, 317000, China
| | - Yi Qiu
- Medical Research Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, 317000, China
| | - Xing-Hong Di
- Medical Research Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, 317000, China
| | - Wei-Wu Shi
- Medical Research Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, 317000, China
| | - Hui-Hui Xu
- Medical Research Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, 317000, China.
| |
Collapse
|
|
8
|
E6/E7 Variants of Human Papillomavirus 16 Associated with Cervical Carcinoma in Women in Southern Mexico. Pathogens 2021; 10:pathogens10060773. [PMID: 34203053 PMCID: PMC8233793 DOI: 10.3390/pathogens10060773] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/18/2021] [Accepted: 06/18/2021] [Indexed: 11/30/2022] Open
Abstract
Persistent infection with the human papillomavirus 16 (HPV 16) is the cause of half of all cervical carcinomas (CC) cases. Moreover, mutations in the oncoproteins E6 and E7 are associated with CC development. In this study, E6/E7 variants circulating in southern Mexico and their association with CC and its precursor lesions were evaluated. In total, 190 DNA samples were obtained from scrapes and cervical biopsies of women with HPV 16 out of which 61 are from patients with CC, 6 from patients with high-grade squamous intraepithelial lesions (HSIL), 68 from patients with low-grade squamous intraepithelial lesions (LSIL), and 55 from patients without intraepithelial lesions. For all E7 variants found, the E7-C732/C789/G795 variant (with three silent mutations) was associated with the highest risk of CC (odd ratio (OR) = 3.79, 95% confidence interval (CI) = 1.46–9.85). The analysis of E6/E7 bicistron conferred to AA-a*E7-C732/C789/G795 variants revealed the greatest increased risk of CC (OR = 110, 95% CI = 6.04–2001.3), followed by AA-c*E7-C732/C789/G795 and A176/G350*E7-p. These results highlight the importance of analyzing the combinations of E6/E7 variants in HPV 16 infection and suggest that AA-a*E7-C732/C789/G795, AA-c*E7-C732/C789/G795, and A176/G350*E7-p can be useful markers for predicting CC development.
Collapse
|
|
9
|
Silva RCDO, da Silva Júnior AHP, Gurgel APAD, Barros Junior MR, Santos DL, de Lima RDCP, Batista MVA, Pena LJ, Chagas BS, Freitas AC. Structural and functional impacts of E5 genetic variants of human papillomavirus type 31. Virus Res 2020; 290:198143. [PMID: 32871208 DOI: 10.1016/j.virusres.2020.198143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/19/2020] [Accepted: 08/21/2020] [Indexed: 11/29/2022]
Abstract
Persistent infections caused by high-risk human papillomavirus (HR-HPV) are important, for the development of cervical lesions, but environmental and genetic factors are also related in the process of carcinogenesis. Among the genetic factors, the genetic variants of HR-HPV appear to be related to the risk of persistent infections. Therefore, the present study investigates variants of HPV31 E5 oncogene in cervical scraping samples from Brazilian women to assess their functional and structural effects, in order to identify possible repercussions of these variants on the infectious and carcinogenic process. Our results detected nucleotide changes previously described in the HPV31 E5 oncogene, which may play a critical role in the development of cancer due to its ability to promote cell proliferation and signal transmission. In our study, the interaction percentage of the 31E5 sequence generated by the Immune Epitope Server database and the Analysis Resource (IEDB) allowed us to include possible immunogenic epitopes with the MHC-I and MHC-II molecules, which may represent a possible relationship between protein suppression of the immune system. In the structural analysis of the HPV31 E5 oncoprotein, the N5D, I48 V, P56A, F80I and V64I polymorphisms can be found inserted within transmembrane regions. The P56A mutation has been predicted to be highly stabilizing and, therefore, can cause a change in protein function. Regarding the interaction of the E5 protein from HPV31 with the signaling of NF-kB pathway, we observed that in all variants of the E5 gene from HPV-31, the activity of the NF-kB pathway was increased compared to the prototype. Our study contributes to a more refined design of studies with the E5 gene from HPV31 and provides important data for a better understanding of how variants can be distinguished under their clinical consequences.
Collapse
Affiliation(s)
- Ruany C de O Silva
- Laboratory of Molecular Studies and Experimental Therapy (LEMTE), Department of Genetics, Federal University of Pernambuco, Pernambuco, Brazil
| | | | - Ana P A D Gurgel
- Department of Engineering and Environment, Federal University of Paraiba, Paraiba, Brazil
| | - Marconi R Barros Junior
- Laboratory of Molecular Studies and Experimental Therapy (LEMTE), Department of Genetics, Federal University of Pernambuco, Pernambuco, Brazil
| | - Daffany L Santos
- Laboratory of Molecular Studies and Experimental Therapy (LEMTE), Department of Genetics, Federal University of Pernambuco, Pernambuco, Brazil
| | - Rita de C P de Lima
- Laboratory of Molecular Studies and Experimental Therapy (LEMTE), Department of Genetics, Federal University of Pernambuco, Pernambuco, Brazil
| | - Marcus V A Batista
- Laboratory of Molecular Genetics and Biotechnology (GMBio), Department of Biology, Federal University of Sergipe, Sergipe, Brazil
| | - Lindomar J Pena
- Department of Virology and Experimental Therapy, Research Center Aggeu Magalhães, Oswaldo Cruz Foundation, Pernambuco, Brazil
| | - Bárbara S Chagas
- Laboratory of Molecular Studies and Experimental Therapy (LEMTE), Department of Genetics, Federal University of Pernambuco, Pernambuco, Brazil
| | - Antonio C Freitas
- Laboratory of Molecular Studies and Experimental Therapy (LEMTE), Department of Genetics, Federal University of Pernambuco, Pernambuco, Brazil.
| |
Collapse
|
|
10
|
Dai S, Li C, Yan Z, Zhou Z, Wang X, Wang J, Sun L, Shi L, Yao Y. Association of Human Papillomavirus Type 16 Long Control Region Variations with Cervical Cancer in a Han Chinese Population. Int J Med Sci 2020; 17:931-938. [PMID: 32308546 PMCID: PMC7163361 DOI: 10.7150/ijms.43030] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 03/07/2020] [Indexed: 12/31/2022] Open
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.
Collapse
Affiliation(s)
- Shuying Dai
- School of Basic Medical Science, Kunming Medical University, Kunming 650500, China
| | - Chuanyin Li
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China
| | - Zhiling Yan
- Department of Gynaecologic Oncology, The 3rd Affiliated Hospital of Kunming Medical University, Kunming 650118, China
| | - Ziyun Zhou
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China
| | - Xia Wang
- Department of Gynaecologic Oncology, The 3rd Affiliated Hospital of Kunming Medical University, Kunming 650118, China
| | - Jun Wang
- Department of Gynaecologic Oncology, The 3rd Affiliated Hospital of Kunming Medical University, Kunming 650118, China
| | - Le Sun
- School of Basic Medical Science, Kunming Medical University, Kunming 650500, China
| | - Li Shi
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China
| | - Yufeng Yao
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China
| |
Collapse
|
|
11
|
Choi YJ, Hur SY, Kim TJ, Hong SR, Lee JK, Cho CH, Park KS, Woo JW, Sung YC, Suh YS, Park JS. A Phase II, Prospective, Randomized, Multicenter, Open-Label Study of GX-188E, an HPV DNA Vaccine, in Patients with Cervical Intraepithelial Neoplasia 3. Clin Cancer Res 2019; 26:1616-1623. [PMID: 31727676 DOI: 10.1158/1078-0432.ccr-19-1513] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 09/08/2019] [Accepted: 11/11/2019] [Indexed: 11/16/2022]
Abstract
PURPOSE To determine the efficacy of the therapeutic DNA vaccine GX-188E for inducing regression of cervical intraepithelial neoplasia (CIN) 3. PATIENTS AND METHODS We conducted a prospective, randomized, multicenter, open-label, phase II clinical trial of GX-188E in CIN3 patients positive for human papillomavirus (HPV) type 16/18. The primary endpoint was to determine the histopathologic regression to ≤CIN1 at visit seven (V7; 20 weeks after the first GX-188E injection), and an extension study was pursued until visit 8 (V8; 36 weeks after the first GX-188E injection). HPV-sequencing analysis and an ex vivo IFNγ ELISpot assay were performed using the collected cervical biopsy and blood samples from patients. RESULTS In total, 72 patients were enrolled and underwent randomization. Of them, 64 patients were included in per-protocol analysis (V7) and 52 in extension analysis (V8). Our data showed 52% (33/64) of patients at V7 and 67% (35/52) of patients at V8 presented histopathologic regression after receiving the GX-188E injection. We found that 73% (V7) and 77% (V8) of the patients with histologic regression showed HPV clearance. HPV clearance and histopathologic regression were significantly associated at V7 and at V8. Compared with the measurements at V1 (baseline), the patients at V8 with HPV clearance showed significantly higher fold changes in their IFNγ ELISpot responses compared with those without HPV clearance. The HPV sequence analysis revealed that the HPV type 16 E6/E7 variants D25E, V83L, and N29S were inversely associated with histopathologic regression at V8. CONCLUSIONS GX-188E is an effective therapeutic vaccine against a cohort containing only CIN3 patients.
Collapse
Affiliation(s)
- Youn Jin Choi
- Department of Obstetrics and Gynecology, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea (South)
- Cancer Research Institute, Department of Medical Lifescience, The Catholic University of Korea, Seoul, Republic of Korea (South)
| | - Soo Young Hur
- Department of Obstetrics and Gynecology, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea (South)
- Cancer Research Institute, Department of Medical Lifescience, The Catholic University of Korea, Seoul, Republic of Korea (South)
| | - Tae-Jin Kim
- Cheil General Hospital, Seoul, Republic of Korea (South)
| | - Sung Ran Hong
- Cheil General Hospital, Seoul, Republic of Korea (South)
| | - Jae Kwan Lee
- Korea University Guro Hospital, Seoul, Republic of Korea (South)
| | - Chi-Heum Cho
- Keimyung University Dongsan Medical Center, Daegu, Republic of Korea (South)
| | - Ki Seok Park
- Genexine, Inc., Seongnam-si, Republic of Korea (South)
| | - Jung Won Woo
- Genexine, Inc., Seongnam-si, Republic of Korea (South)
| | - Young Chul Sung
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Gyeonggbuk, Republic of Korea (South)
| | - You Suk Suh
- Genexine, Inc., Seongnam-si, Republic of Korea (South).
| | - Jong Sup Park
- Department of Obstetrics and Gynecology, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea (South).
- Genexine, Inc., Seongnam-si, Republic of Korea (South)
| |
Collapse
|
|
12
|
Gheit T. Mucosal and Cutaneous Human Papillomavirus Infections and Cancer Biology. Front Oncol 2019; 9:355. [PMID: 31134154 PMCID: PMC6517478 DOI: 10.3389/fonc.2019.00355] [Citation(s) in RCA: 199] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 04/17/2019] [Indexed: 12/13/2022] Open
Abstract
Papillomaviridae is a family of small non-enveloped icosahedral viruses with double-stranded circular DNA. More than 200 different human papillomaviruses (HPVs) have been listed so far. Based on epidemiological data, a subgroup of alphapapillomaviruses (alpha HPVs) was referred to as high-risk (HR) HPV types. HR HPVs are the etiological agents of anogenital cancer and a subset of head and neck cancers. The cutaneous HPV types, mainly from beta and gamma genera, are widely present on the surface of the skin in the general population. However, there is growing evidence of an etiological role of betapapillomaviruses (beta HPVs) in non-melanoma skin cancer (NMSC), together with ultraviolet (UV) radiation. Studies performed on mucosal HR HPV types, such as 16 and 18, showed that both oncoproteins E6 and E7 play a key role in cervical cancer by altering pathways involved in the host immune response to establish a persistent infection and by promoting cellular transformation. Continuous expression of E6 and E7 of mucosal HR HPV types is essential to initiate and to maintain the cellular transformation process, whereas expression of E6 and E7 of cutaneous HPV types is not required for the maintenance of the skin cancer phenotype. Beta HPV types appear to play a role in the initiation of skin carcinogenesis, by exacerbating the accumulation of UV radiation-induced DNA breaks and somatic mutations (the hit-and-run mechanism), and they would therefore act as facilitators rather than direct actors in NMSC. In this review, the natural history of HPV infection and the transforming properties of various HPV genera will be described, with a particular focus on describing the state of knowledge about the role of cutaneous HPV types in NMSC.
Collapse
Affiliation(s)
- Tarik Gheit
- Infections and Cancer Biology Group, International Agency for Research on Cancer (IARC), Lyon, France
| |
Collapse
|
|
13
|
Zhou Z, Yang H, Yang L, Yao Y, Dai S, Shi L, Li C, Yang L, Yan Z, Yao Y. Human papillomavirus type 16 E6 and E7 gene variations associated with cervical cancer in a Han Chinese population. INFECTION GENETICS AND EVOLUTION 2019; 73:13-20. [PMID: 30981880 DOI: 10.1016/j.meegid.2019.04.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Revised: 04/09/2019] [Accepted: 04/10/2019] [Indexed: 10/27/2022]
Abstract
BACKGROUD Human papillomavirus type 16 (HPV16) is a high-risk HPV subtype and a potent carcinogen. The HPV16 E6 and E7 genes are considered oncogenes that play a core role in the development of cervical cancer. METHODS In the current study, we enrolled 97 HPV16-positive cervical cancer patients (case group) and 136 HPV16-positive asymptomatic individuals (control group) in a study to analyse the association between HPV16 E6 and E7 gene variations and cervical cancer. RESULTS Our results showed that three HPV16 sub-lineages (A1-A3, A4 and D3) were present; the distribution of these variants between the case and control group was not significantly different (P = 0.178). When the distribution of the HPV16 E6 and E7 gene variations was compared, the distribution of only A131C (R10R) in the E6 gene showed a different trend between the case and control groups and C749T (S63F) in the E7 gene was significantly different between the case and control groups (P = 0.071 and P = 4.861 × 10-10, respectively). Regarding the sub-lineages, no variations in the E6 gene were significantly different between the case and control group for the A4 (As) and A1-A3 (EUR) sub-lineages. However, the distribution of C749T (S63F) in the E7 gene was significantly different between the case and control groups for the A4 (As) and A1-A3 (EUR) sub-lineages (P = 1.815 × 10-8 and P = 0.008). In the current study, we found that the C749T (S63F) variation in the HPV16 E7 gene was associated with cervical cancer not only in the A4 (As) sub-lineage but also in the A1-A3 (EUR) sub-lineage. CONCLUSION Our study will provide a good reference for further functional studies of the relationship between cervical cancer carcinogenesis and the HPV16 E6 and E7 genes.
Collapse
Affiliation(s)
- Ziyun Zhou
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, Yunnan, China
| | - Hongying Yang
- Department of Gynaecologic Oncology, The 3rd Affiliated Hospital of Kunming Medical University, Kunming 650118, China
| | - Lijuan Yang
- Department of Gynaecologic Oncology, The 3rd Affiliated Hospital of Kunming Medical University, Kunming 650118, China
| | - Yueting Yao
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, Yunnan, China
| | - Shuying Dai
- School of Basic Medical Science, Kunming Medical University, Kunming 650500, China
| | - Li Shi
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, Yunnan, China
| | - Chuanyin Li
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, Yunnan, China
| | - Longyu Yang
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, Yunnan, China
| | - Zhiling Yan
- Department of Gynaecologic Oncology, The 3rd Affiliated Hospital of Kunming Medical University, Kunming 650118, China.
| | - Yufeng Yao
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, Yunnan, China.
| |
Collapse
|
|
14
|
Galati L, Equestre M, Bruni R, Accardi L, Torti C, Fiorillo MT, Surace G, Barreca GS, Liberto MC, Focà A, Ciccaglione AR, Di Bonito P. Identification of human papillomavirus type 16 variants circulating in the Calabria region by sequencing and phylogenetic analysis of HPV16 from cervical smears. INFECTION GENETICS AND EVOLUTION 2018; 68:185-193. [PMID: 30578936 DOI: 10.1016/j.meegid.2018.12.024] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 12/17/2018] [Accepted: 12/18/2018] [Indexed: 02/04/2023]
Abstract
Sequence analysis of HPV16 isolates reveals the presence of genome variants with characteristic mutations. The HPV16 variants have different geographical distribution and diverge into four phylogenetic lineages (A, B, C and D) and 16 sub-lineages: A1, A2, A3 (previously known as European variants), A4 (Asian variant), B1, B2, B3, B4, C1, C2, C3, and C4 (African variants), D1 (North-American variant), D2, D3 (Asian-American variants) and D4. Population studies showed that infections with viruses belonging to specific HPV16 sublineages confer different risks of viral persistence and cancer. In this study, 39 HPV16-positive cervical smears from European women living in Calabria (Italy) were analyzed for the presence of HPV16 variants. Cervical DNA extracts were processed by PCR to amplify L1, the Long Control Region (LCR), E6 and E7, which were sequenced. The sequences were concatenated and the 3169 nucleotides long fragments were characterized by BLAST and phylogenetic analysis. A total of 96 Single Nucleotide Polymorphism (SNPs) were detected, 29 of which mapping in the L1, 45 in the LCR, 15 in the E6 and 7 in the E7. The most common SNP was the T350G (29/39 samples, 74.4%), causing the L83 V amino acid change in the E6. Most of the HPV16 isolates (89.7%) had 99% of nucleotide (nt) identity to members of the A1 and A2 sublineages, while 4 isolates had 99% nt identity to members of the B2, B4, C1 and D4 sublineages. In conclusion, viruses belonging to the A1, A2, B2, B4, C1 and D4 HPV16 sublineages were found to circulate in the Calabria region.
Collapse
Affiliation(s)
- Luisa Galati
- Department Infectious Diseases, EVOR unit, Istituto Superiore di Sanità, Rome, Italy; Institute of Clinical Microbiology, Department of Health Sciences, "Magna Graecia" University, Catanzaro, Italy
| | - Michele Equestre
- Department Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
| | - Roberto Bruni
- Department Infectious Diseases, EVOR unit, Istituto Superiore di Sanità, Rome, Italy
| | - Luisa Accardi
- Department Infectious Diseases, EVOR unit, Istituto Superiore di Sanità, Rome, Italy
| | - Carlo Torti
- Department of Medical and Surgical Sciences, Unit of Infectious and Tropical Diseases, School of Medicine, University of "Magna Graecia", Catanzaro, Italy
| | - Maria Teresa Fiorillo
- Unit of Microbiology and Virology, Polo Sanitario Nord ASP 5, Reggio Calabria, Italy
| | - Giovanni Surace
- Unit of Microbiology and Virology, Polo Sanitario Nord ASP 5, Reggio Calabria, Italy
| | - Giorgio Settimo Barreca
- Institute of Clinical Microbiology, Department of Health Sciences, "Magna Graecia" University, Catanzaro, Italy
| | - Maria Carla Liberto
- Institute of Clinical Microbiology, Department of Health Sciences, "Magna Graecia" University, Catanzaro, Italy
| | - Alfredo Focà
- Institute of Clinical Microbiology, Department of Health Sciences, "Magna Graecia" University, Catanzaro, Italy
| | - Anna Rita Ciccaglione
- Department Infectious Diseases, EVOR unit, Istituto Superiore di Sanità, Rome, Italy
| | - Paola Di Bonito
- Department Infectious Diseases, EVOR unit, Istituto Superiore di Sanità, Rome, Italy.
| |
Collapse
|
|
15
|
Combes JD, Franceschi S. Human papillomavirus genome variants and head and neck cancers: a perspective. Infect Agent Cancer 2018; 13:13. [PMID: 29643933 PMCID: PMC5891965 DOI: 10.1186/s13027-018-0185-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 03/27/2018] [Indexed: 12/22/2022] Open
Abstract
Human papillomaviruses (HPV) cause infections that are responsible for diverse clinical manifestations from benign conditions to invasive cancer. As different HPV types are associated with variable pathogenic potential, minor genetic variations within a given high-risk HPV type might also be associated with distinct oncogenic capacities, through variable ability of persistence or risk of progression to precancer/cancer. Most recent HPV variant studies in the cervix using latest sequencing technology confirmed that minor changes in the HPV genome can have a major influence on carcinogenesis and have revealed key data that help better understand the carcinogenicity of HPV at a molecular level. Here we review the limited number of studies on HPV genome variants in head and neck cancers (HNC) and discuss their implications for cancer research in the light of accumulated knowledge for the cervix. Challenges in transposing HPV variant studies from the lower anogenital to the upper aerodigestive tract are also discussed, highlighting the main gaps of knowledge in the field of HPV-induced HNC. Specifically in the head and neck region, the lack of characterisation of precancerous lesions and the difficulty in sampling normal tissue will challenge the development of accurate studies. Although there is so far no indication that HPV variant research in HNC could directly translate into clinical application, such research is expected to be useful to disentangle unanswered questions in the pathogenesis of HNC. Yet, history of HPV variant research suggests that, to be successful, studies will require large international collaborative efforts.
Collapse
Affiliation(s)
- Jean-Damien Combes
- International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Cedex 08 Lyon, France
| | - Silvia Franceschi
- Cancer Epidemiology Unit, CRO Aviano National Cancer Institute IRCCS, Via Franco Gallini 2, 33081 Aviano, PN Italy
| |
Collapse
|
|
16
|
King AJ, Sonsma JA, Vriend HJ, van der Sande MAB, Feltkamp MC, Boot HJ, Koopmans MPG. Genetic Diversity in the Major Capsid L1 Protein of HPV-16 and HPV-18 in the Netherlands. PLoS One 2016; 11:e0152782. [PMID: 27070907 PMCID: PMC4829201 DOI: 10.1371/journal.pone.0152782] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 03/18/2016] [Indexed: 11/25/2022] Open
Abstract
Objectives Intratypic molecular variants of human papillomavirus (HPV) type-16 and -18 exist. In the Netherlands, a bivalent vaccine, composed of recombinant L1 proteins from HPV-16 and -18, is used to prevent cervical cancer since 2009. Long-term vaccination could lead to changes in HPV-16 and -18 virus population, thereby hampering vaccination strategies. We determined the genetic diversity of the L1 gene in HPV-16 and -18 viral strains circulating in the Netherlands at the start of vaccination in order to understand the baseline genetic diversity in the Dutch population. Methods DNA sequences of the L1 gene were determined in HPV-16 (n = 241) and HPV-18 (n = 108) positive anogenital samples collected in 2009 and 2011 among Dutch 16- to 24-year old female and male attendees of the sexually transmitted infection (STI) clinics. Phylogenetic analysis was performed and sequences were compared to reference sequences HPV-16 (AF536179) and HPV-18 (X05015) using BioNumerics 7.1. Results For HPV-16, ninety-five single nucleotide polymorphism (SNPs) were identified, twenty–seven (28%) were non-synonymous variations. For HPV-18, seventy-one SNPs were identified, twenty-nine (41%) were non-synonymous. The majority of the non-silent variations were located in sequences encoding alpha helix, beta sheet or surface loops, in particular in the immunodominant FG loop, and may influence the protein secondary structure and immune recognition. Conclusions This study provides unique pre-vaccination/baseline data on the genetic L1 diversity of HPV-16 and -18 viruses circulating in the Netherlands among adolescents and young adults.
Collapse
Affiliation(s)
- Audrey J. King
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
- * E-mail:
| | - Jan A. Sonsma
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Henrike J. Vriend
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Marianne A. B. van der Sande
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
- Julius Centre for Primary Care and Public Health, University Medical Centre, Utrecht, The Netherlands
| | - Mariet C. Feltkamp
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Hein J. Boot
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Marion P. G. Koopmans
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | | |
Collapse
|
|
17
|
Kumar A, Hussain S, Sharma G, Mehrotra R, Gissmann L, Das BC, Bharadwaj M. Identification and validation of immunogenic potential of India specific HPV-16 variant constructs: In-silico &in-vivo insight to vaccine development. Sci Rep 2015; 5:15751. [PMID: 26507515 PMCID: PMC4623767 DOI: 10.1038/srep15751] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 07/21/2015] [Indexed: 11/15/2022] Open
Abstract
Cervical cancer is one of the most common gynecological cancers in the world but in India, it is the top most cancer among women. Persistent infection with high-risk human papillomaviruses (HR-HPVs) is the most important risk factor. The sequence variation(s) in the most common HR-HPV i.e. HPV type 16 leads to altered biological functions with possible clinical significance in the different geographical locations. Sixteen major variants (V1-V16) in full length L1 gene of HPV-16 were identified following analysis of 250 prospectively collected cervical cancer tissue biopsies and their effect on immunogenicity was studied. The effect of these major variations on the epitopes were predicted by in silico methods and the immunogenicity of variants and respective reference DNA vaccine constructs were evaluated by administration of prepared DNA vaccine constructs in female BALB/c mice to evaluate antibody titer. In the present study, L500F (V16) variation showed a significant ~2.7 fold (p < 0.002) increase in antibody titer, whereas T379P (V8) showed ~0.4 fold (p < 0.328) decrease after final injection. These results showed a promising roadmap for the development of DNA based vaccine and for the generation of effective response, though there is a need to study more prevalent variants of HPV in the Indian population.
Collapse
Affiliation(s)
- Anoop Kumar
- Division of Molecular Genetics & Biochemistry; Noida, Uttar Pradesh, India
- Dr. B.R. Ambedkar center for Biomedical Research, University of Delhi (North Campus), New Delhi, India
| | - Showket Hussain
- Division of Molecular Genetics & Biochemistry; Noida, Uttar Pradesh, India
| | - Gagan Sharma
- Division of Molecular Genetics & Biochemistry; Noida, Uttar Pradesh, India
| | - Ravi Mehrotra
- Division of Cytopathology; Institute of Cytology & Preventive Oncology (ICMR), Noida, Uttar Pradesh, India
| | - Lutz Gissmann
- Division of Genome Modification and Carcinogenesis, German Cancer Center, DKFZ Heidelberg, Germany
| | - Bhudev C. Das
- Dr. B.R. Ambedkar center for Biomedical Research, University of Delhi (North Campus), New Delhi, India
| | - Mausumi Bharadwaj
- Division of Molecular Genetics & Biochemistry; Noida, Uttar Pradesh, India
| |
Collapse
|
|
18
|
Mejía L, Muñoz D, Trueba G, Tinoco L, Zapata S. Prevalence of human papillomavirus types in cervical cancerous and precancerous lesions of Ecuadorian women. J Med Virol 2015; 88:144-52. [PMID: 26113443 DOI: 10.1002/jmv.24310] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/22/2015] [Indexed: 11/06/2022]
Abstract
Human Papillomavirus (HPV) is the most common sexually transmitted infection worldwide and it is responsible for most cases of uterine cancer. In Ecuador there is limited information about HPV types (and variants) in cancerous lesions; however, identifying the type-specific HPV prevalence in cervical lesions of women living in Ecuador is important to better predict the impact of HPV prophylactic vaccination in this country. We studied the prevalence of HPV types in cervical cancerous or precancerous lesions from 164 Ecuadorian women and found that 86.0% were HPV positive. The most common types were HPV16 (41.8%) and HPV58 (30.5%). Interestingly, HPV18 was detected only in 2.8% of the HPV-positive samples. Fifteen DNA sequences (genes E6 and L1) from 16 samples positive for HPV16 belonged to the European lineage, considered one of the least carcinogenic lineages, and 1 (6.25%) to the Asian-American lineage. Similar analysis in 12 HPV58 positive samples showed that 10 (83.3%) sequences grouped in sublineage A2, which belongs to the oldest HPV58 lineage, 1 belonged to A3 and 1 to lineage C. This study suggests that the currently used HPV vaccines (bivalent and tetravalent) may have lower effectiveness in Ecuador than in other geographic locations where HPV18 is more prevalent.
Collapse
Affiliation(s)
- Lorena Mejía
- Instituto de Microbiología, Universidad San Francisco de Quito, Quito, Ecuador
| | - Diana Muñoz
- Instituto de Microbiología, Universidad San Francisco de Quito, Quito, Ecuador
| | - Gabriel Trueba
- Instituto de Microbiología, Universidad San Francisco de Quito, Quito, Ecuador
| | - Leopoldo Tinoco
- Unidad de Ginecología y Colposcopía, Hospital SOLCA, Quito, Ecuador
| | - Sonia Zapata
- Instituto de Microbiología, Universidad San Francisco de Quito, Quito, Ecuador
| |
Collapse
|
|
19
|
Association Study between Cervical Lesions and Single or Multiple Vaccine-Target and Non-Vaccine Target Human Papillomavirus (HPV) Types in Women from Northeastern Brazil. PLoS One 2015; 10:e0132570. [PMID: 26176537 PMCID: PMC4503727 DOI: 10.1371/journal.pone.0132570] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Accepted: 06/16/2015] [Indexed: 01/05/2023] Open
Abstract
We performed an association between high-grade squamous intraepithelial lesions (HSIL), low-grade squamous intraepithelial lesions (LSIL) and single or multiple vaccine-target as well as non-vaccine target Human papillomavirus (HPV) types. Using bead-based HPV genotyping, 594 gynecological samples were genotyped. An association between squamous intraepithelial lesion (SIL) and presence of HPV16, 18, 31, 58 and 56 types were calculated. The risk was estimated by using odds ratio (OR) and 95% of confidence intervals (CI). A total of 370 (62.3%) women were HPV positive. Among these, 157 (42.7%) presented a single HPV infection, and 212 (57.3%) were infected by more than one HPV type. HPV31 was the most prevalent genotype, regardless single and multiple HPV infections. Single infection with HPV31 was associated with LSIL (OR=2.32; 95%CI: 1.01 to 5.32; p=0.04); HPV31 was also associated with LSIL (OR=3.28; 95%CI: 1.74 to 6.19; p= 0.0002) and HSIL (OR=3.82; 95%CI: 2.10 to 6.97; p<0.001) in multiple HPV infections. Risk to harbor cervical lesions was observed in multiple HPV infections with regard to the HPV56 (OR=5.39; 95%CI: 2.44 to 11.90; p<0.001for LSIL; OR=5.37; 95%CI: 2.71 to 10.69; p<0.001) and HPV58 (OR=3.29; 95%CI: 1.34 to 8.09; p=0.0091 for LSIL; OR=3.55; 95%CI: 1.56 to 8.11; p=0.0026) genotypes. In addition, women coinfected with HPV16/31/56 types had 6 and 5-fold increased risk of HSIL (OR=6.46; 95%CI: 1.89 to 22.09; p=0.002) and LSIL (OR=5.22; 95%CI: 1.10 to 24.70; p=0.03), respectively. Multiple HPV infections without HPV16/18 has 2-fold increased risk of HSIL (OR=2.57; 95%CI: 1.41 to 4.70; p=0.002) and LSIL OR=2.03; 95%CI: 1.08 to 3.79; p=0.02). The results of this study suggest that single and multiple vaccine target as well as non-vaccine target HPV types are associated with LSIL and HSIL. These finding should be taken into consideration in the design of HPV vaccination strategies.
Collapse
|
|
20
|
Prevalence of human papillomavirus variants and genetic diversity in the L1 gene and long control region of HPV16, HPV31, and HPV58 found in North-East Brazil. BIOMED RESEARCH INTERNATIONAL 2015; 2015:130828. [PMID: 25793187 PMCID: PMC4352477 DOI: 10.1155/2015/130828] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Accepted: 01/08/2015] [Indexed: 02/06/2023]
Abstract
This study showed the prevalence of human papillomavirus (HPV) variants as well as nucleotide changes within L1 gene and LCR of the HPV16, HPV31, and HPV58 found in cervical lesions of women from North-East Brazil.
Collapse
|
|
21
|
Lopera EA, Baena A, Florez V, Montiel J, Duque C, Ramirez T, Borrero M, Cordoba CM, Rojas F, Pareja R, Bedoya AM, Bedoya G, Sanchez GI. Unexpected inverse correlation between Native American ancestry and Asian American variants of HPV16 in admixed Colombian cervical cancer cases. INFECTION GENETICS AND EVOLUTION 2014; 28:339-48. [PMID: 25446942 DOI: 10.1016/j.meegid.2014.10.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Revised: 09/18/2014] [Accepted: 10/16/2014] [Indexed: 12/17/2022]
Abstract
BACKGROUND European (E) variants of HPV 16 are evenly distributed among world regions, meanwhile Non-European variants such as European-Asian (EAs), Asian American (AA) and African (Af) are mostly confined to Eastern Asia, The Americas and African regions respectively. Several studies have shown that genetic variation of HPV 16 is associated with the risk of cervical cancer, which also seems to be dependent on the population. This relationship between ethnicity and variants have led to the suggestion that there is co-evolution of variants with humankind. Our aim was to evaluate the relationship between the individual ancestry proportion and infection with HPV 16 variants in cervical cancer. METHODS We examined the association between ancestry and HPV 16 variants in samples of 82 cervical cancer cases from different regions of Colombia. Individual ancestry proportions (European, African and Native American) were estimated by genotyping 106 ancestry informative markers. Variants were identified by PCR amplification of the E6 gene, followed by reverse line blot hybridization (RLB) with variants specific probes. RESULTS Overall European (E) and Asian American (AA) variants frequency was 66.5% and 33.5% respectively. Similar distribution was observed in cases with higher proportions of European or African ancestry. A higher Native American ancestry was significantly associated with higher frequency of E variants (median ancestry>23.6%, Age and place of birth adjusted OR: 3.55, 95% CI: 1.26-10.03, p=0.01). Even further, an inverse geographic correlation between Native American ancestry and frequency of infections with AA variants was observed (ρ=-0.825, p=0.008). Regions with higher proportion of Native American ancestry had a lower frequency of AA variants of HPV 16. CONCLUSIONS This study suggests replacement of AA variants by E variants of human papillomavirus 16 in cervical cancer cases with high Native American ancestry.
Collapse
Affiliation(s)
- Esteban A Lopera
- Infection and Cancer Group, School of Medicine and Corporación Académica para el Estudio de Patologías Tropicales, Universidad de Antioquia, UdeA, Calle 70 No 52-21, Medellín, Colombia
| | - Armando Baena
- Infection and Cancer Group, School of Medicine and Corporación Académica para el Estudio de Patologías Tropicales, Universidad de Antioquia, UdeA, Calle 70 No 52-21, Medellín, Colombia
| | - Victor Florez
- Infection and Cancer Group, School of Medicine and Corporación Académica para el Estudio de Patologías Tropicales, Universidad de Antioquia, UdeA, Calle 70 No 52-21, Medellín, Colombia
| | - Jehidys Montiel
- Infection and Cancer Group, School of Medicine and Corporación Académica para el Estudio de Patologías Tropicales, Universidad de Antioquia, UdeA, Calle 70 No 52-21, Medellín, Colombia
| | - Constanza Duque
- Genética Molecular, Universidad de Antioquia, UdeA, Calle 70 No 52-21, Medellín, Colombia; Universidad Cooperativa de Colombia, Carrera 42 No 49-95, Medellín, Colombia
| | - Tatiana Ramirez
- Infection and Cancer Group, School of Medicine and Corporación Académica para el Estudio de Patologías Tropicales, Universidad de Antioquia, UdeA, Calle 70 No 52-21, Medellín, Colombia
| | - Mauricio Borrero
- Infection and Cancer Group, School of Medicine and Corporación Académica para el Estudio de Patologías Tropicales, Universidad de Antioquia, UdeA, Calle 70 No 52-21, Medellín, Colombia; Instituto de Cancerología Las Américas, Carrera 70 No 1-35, Torre 5, Medellín, Colombia; Department of Gynecology and Obstetrics, School of Medicine, Universidad de Antioquia, UdeA, Calle 70 No 52-52, Medellín, Colombia
| | - Carlos M Cordoba
- Department of Gynecology and Obstetrics, School of Medicine, Universidad de Antioquia, UdeA, Calle 70 No 52-52, Medellín, Colombia
| | - Fredy Rojas
- Instituto de Cancerología Las Américas, Carrera 70 No 1-35, Torre 5, Medellín, Colombia
| | - Rene Pareja
- Instituto de Cancerología Las Américas, Carrera 70 No 1-35, Torre 5, Medellín, Colombia
| | - Astrid M Bedoya
- Infection and Cancer Group, School of Medicine and Corporación Académica para el Estudio de Patologías Tropicales, Universidad de Antioquia, UdeA, Calle 70 No 52-21, Medellín, Colombia; Escuela de Microbiología, Universidad de Antioquia UdeA, Calle 70 No 52-21, Medellín, Colombia
| | - Gabriel Bedoya
- Genética Molecular, Universidad de Antioquia, UdeA, Calle 70 No 52-21, Medellín, Colombia
| | - Gloria I Sanchez
- Infection and Cancer Group, School of Medicine and Corporación Académica para el Estudio de Patologías Tropicales, Universidad de Antioquia, UdeA, Calle 70 No 52-21, Medellín, Colombia.
| |
Collapse
|
|
22
|
Human papillomavirus 16 non-European variants are preferentially associated with high-grade cervical lesions. PLoS One 2014; 9:e100746. [PMID: 24983739 PMCID: PMC4077691 DOI: 10.1371/journal.pone.0100746] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Accepted: 05/29/2014] [Indexed: 01/10/2023] Open
Abstract
HPV16 accounts for 50–70% of cervical cancer cases worldwide. Characterization of HPV16 variants previously indicated that they differ in risks for viral persistence, progression to cervical precancer and malignant cancer. The aim of this study was to examine the association of severity of disease with HPV16 variants identified in specimens (n = 281) obtained from a Cervical Pathology and Colposcopy outpatient clinic in the University Hospital of Espírito Santo State, Southeastern Brazil, from April 2010 to November 2011. All cytologic and histologic diagnoses were determined prior to definitive treatment. The DNA was isolated using QIAamp DNA Mini Kit and HPV was detected by amplification with PGMY09/11 primers and positive samples were genotyped by RFLP analyses and reverse line blot. The genomes of the HPV16 positive samples were sequenced, from which variant lineages were determined. Chi2 statistics was performed to test the association of HPV16 variants between case and control groups. The prevalence of HR-HPV types in <CIN1, CIN2 and CIN3+ were 33.7%, 84.4% and 91.6%, respectively. Thirty-eight of 49 (78%) HPV16 positive samples yielded HPV16 sequence information; of which, 32 complete genomes were sequenced and an additional 6 samples were partially sequenced. Phylogenetic analysis and patterns of variations identified 65.8% (n = 25) as HPV16 European (E) and 34.2% (n = 13) as non-European (NE) variants. Classification of disease into CIN3+ vs. <CIN3 indicated that NE types were associated with high-grade disease with an OR = 4.6 (1.07–20.2, p = 0.05). The association of HPV16 NE variants with an increased risk of CIN3+ is consistent with an HPV16 genetically determined enhanced oncogenicity. The prevalence of genetic variants of HPV16 is distributed across different geographical areas and with recent population admixture, only empiric data will provide information on the highest risk HPV16 variants within a given population.
Collapse
|
|
23
|
Woods RSR, O’Regan EM, Kennedy S, Martin C, O’Leary JJ, Timon C. Role of human papillomavirus in oropharyngeal squamous cell carcinoma: A review. World J Clin Cases 2014; 2:172-193. [PMID: 24945004 PMCID: PMC4061306 DOI: 10.12998/wjcc.v2.i6.172] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Revised: 04/21/2014] [Accepted: 05/19/2014] [Indexed: 02/05/2023] Open
Abstract
Human papillomavirus (HPV) has been implicated in the pathogenesis of a subset of oropharyngeal squamous cell carcinoma. As a result, traditional paradigms in relation to the management of head and neck squamous cell carcinoma have been changing. Research into HPV-related oropharyngeal squamous cell carcinoma is rapidly expanding, however many molecular pathological and clinical aspects of the role of HPV remain uncertain and are the subject of ongoing investigation. A detailed search of the literature pertaining to HPV-related oropharyngeal squamous cell carcinoma was performed and information on the topic was gathered. In this article, we present an extensive review of the current literature on the role of HPV in oropharyngeal squamous cell carcinoma, particularly in relation to epidemiology, risk factors, carcinogenesis, biomarkers and clinical implications. HPV has been established as a causative agent in oropharyngeal squamous cell carcinoma and biologically active HPV can act as a prognosticator with better overall survival than HPV-negative tumours. A distinct group of younger patients with limited tobacco and alcohol exposure have emerged as characteristic of this HPV-related subset of squamous cell carcinoma of the head and neck. However, the exact molecular mechanisms of carcinogenesis are not completely understood and further studies are needed to assist development of optimal prevention and treatment modalities.
Collapse
|
|
24
|
Marongiu L, Godi A, Parry JV, Beddows S. Human papillomavirus type 16 long control region and E6 variants stratified by cervical disease stage. INFECTION GENETICS AND EVOLUTION 2014; 26:8-13. [PMID: 24823962 PMCID: PMC4150919 DOI: 10.1016/j.meegid.2014.05.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Revised: 04/30/2014] [Accepted: 05/05/2014] [Indexed: 01/08/2023]
Abstract
We sequenced HPV16 LCR–E6 variants in cervical disease samples from England. 98% of variants were of the EUR lineage. Site-specific entropy identified several variable sites in the LCR and E6. No single or combination of sites were associated with disease, including E6 T350G. Objective Certain intra-type variants of HPV16 have been shown to be associated with an increased risk of developing high grade cervical disease, but their potential association is confounded by apparent geographic and phylogenetic lineage dependency. The objective of this study was to evaluate the relationship between HPV16 sequence variants and cervical disease stage in monospecific infection samples from a single lineage (European, EUR) in England. Methods One hundred and twelve women singly infected with HPV16 and displaying normal and abnormal cytology grades were selected. An 1187 bp fragment encompassing the entire LCR and a portion of the E6 open reading frame was sequenced to identify intra-type variants. Intra-type diversity was estimated using Shannon entropy. Results Almost all samples (110/112; 98%) were assigned to the EUR lineage, one sample was classified as European-Asian (EAS) and another African (Afr1a). The mean pairwise distance of the EUR sequences in this study was low (0.29%; 95%CI 0.13–0.45%) but there were nevertheless several sites in the LCR (n = 5) and E6 (n = 2) that exhibited a high degree of entropy. None of these sites, however, including the T350G non-synonymous (L83V) substitution in E6, alone or in combination, were found to be associated with cervical disease stage. Conclusions Despite using single infection samples and samples from a single variant lineage, intra-type variants of HPV16 were not differentially associated with cervical disease. Monitoring intra-lineage, site-specific variants, such as T350G, is unlikely to be of diagnostic value.
Collapse
Affiliation(s)
- Luigi Marongiu
- Virus Reference Department, Public Health England, London, UK
| | - Anna Godi
- Virus Reference Department, Public Health England, London, UK
| | - John V Parry
- Virus Reference Department, Public Health England, London, UK
| | - Simon Beddows
- Virus Reference Department, Public Health England, London, UK.
| |
Collapse
|
|
25
|
Burk RD, Harari A, Chen Z. Human papillomavirus genome variants. Virology 2013; 445:232-43. [PMID: 23998342 DOI: 10.1016/j.virol.2013.07.018] [Citation(s) in RCA: 316] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Revised: 07/15/2013] [Accepted: 07/17/2013] [Indexed: 11/27/2022]
Abstract
Amongst the human papillomaviruses (HPVs), the genus Alphapapillomavirus contains HPV types that are uniquely pathogenic. They can be classified into species and types based on genetic distances between viral genomes. Current circulating infectious HPVs constitute a set of viral genomes that have evolved with the rapid expansion of the human population. Viral variants were initially identified through restriction enzyme polymorphisms and more recently through sequence determination of viral fragments. Using partial sequence information, the history of variants, and the association of HPV variants with disease will be discussed with the main focus on the recent utilization of full genome sequence information for variant analyses. The use of multiple sequence alignments of complete viral genomes and phylogenetic analyses have begun to define variant lineages and sublineages using empirically defined differences of 1.0-10.0% and 0.5-1.0%, respectively. These studies provide the basis to define the genetics of HPV pathogenesis.
Collapse
Affiliation(s)
- Robert D Burk
- Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx 10461, NY, USA; Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx 10461, NY, USA; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx 10461, NY, USA; Department of Obstetrics, Gynecology and Women's Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx 10461, NY, USA.
| | | | | |
Collapse
|
|
26
|
Lai ZZ, Ni-Zhang, Pan XL, Song L. Toll-like receptor 9 (TLR9) gene polymorphisms associated with increased susceptibility of human papillomavirus-16 infection in patients with cervical cancer. J Int Med Res 2013; 41:1027-36. [PMID: 23816930 DOI: 10.1177/0300060513483398] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Objectives To investigate the association between toll-like receptor 9 ( TLR9) single nucleotide polymorphisms (SNPs) and human papillomavirus (HPV) infection among Chinese Han women with cervical cancer. Methods TLR9 –1486 and 2848 SNPs were investigated in patients with cervical cancer and controls using polymerase chain reaction (PCR)-restriction fragment length polymorphism. HPV16 E6 and E7 infections were assessed using PCR. Results Of 120 patients with cervical cancer and 100 controls, there was a significant association between TLR9 2848 SNP and cervical cancer risk, but there was no such association with TLR9 –1486 SNP. Frequency of the TLR9 2848 GA genotype was significantly higher in patients with cervical cancer than in controls. There was no statistically significant between-group difference in presence of HPV16 infection. Presence of HPV infection with TLR9 2848 (rs352140) GA/AA genotype increased the risk of cervical cancer 13.8-fold compared with the GG genotype. Conclusions The TLR9 2848 G/A polymorphism in Chinese Han women was associated with increased risk of cervical cancer in the presence of HPV16 infection. Further studies are necessary to uncover the functional aspect of this TLR9 2848 polymorphism.
Collapse
Affiliation(s)
- Zeng-Zhen Lai
- Department of Obstetrics and Gynaecology, West China Second Hospital, Sichuan University, Chengdu, China
- Department of Obstetrics and Gynaecology, People’s Hospital of Deyang City, Deyang, China
| | - Ni-Zhang
- Department of Obstetrics and Gynaecology, West China Second Hospital, Sichuan University, Chengdu, China
| | - Xiao-Ling Pan
- Department of Obstetrics and Gynaecology, West China Second Hospital, Sichuan University, Chengdu, China
| | - Liang Song
- Department of Obstetrics and Gynaecology, West China Second Hospital, Sichuan University, Chengdu, China
| |
Collapse
|