Dataset Information

Different Association of Human Papillomavirus 16 Variants with Early and Late Presentation of Cervical Cancer.

ABSTRACT: The median age of cervical cancer (CC) presentation coincides with the mean age of menopause presentation (49 years) in Mexico. Here, we investigated the association between different HPV16 variants and early (? 49 years) or delayed (? 50 years) CC presentation. We conducted a case-case study that included 462 CCs, 386 squamous cell carcinomas (SCC), 63 adenocarcinomas (ACC), and 13 additional cell types. Variants were identified by PCR and DNA sequencing. The risk conferred by each variant for developing CC earlier than 50 years was analyzed using a univariate logistic regression model considering old-aged patients (? 50 years) and non-HPV16 cases as the reference variables. Overall, the frequency of HPV16 was 50.9%, and the only identified variants were the European A1/2 (31.2%) and the Asian-American D2 (10.8%), and D3 (8.9%). D2 was mainly associated with ? 49-year-old patients (15.9%); A1/2 was uniformly distributed between the two age groups (~31%), whereas D3 increased with age to a frequency of 11.8% in the older group. Only the D2 variant conferred a 3.3-fold increase in the risk of developing CC before 50 years of age (OR = 3.3, 95% CI = 1.7-6.6, p < 0.001) in relation with non-HPV16 cases. Remarkably, this risk was higher for ACC (OR = 6.0, 95% CI = 1.1-33, p < 0.05) than for SCC (OR = 2.8, 95% CI = 1.3-5.9, p < 0.01). Interestingly, when analyzing only the HPV16-positive CC, D2 increases (OR = 2.5, 95% CI = 1.2-5, p < 0.05) and D3 decreases (OR = 0.45, 95% CI 0.2-0.9, p < 0.05) the risk to develop CC before 50 years old in relation with A1/2 variant. These results indicated that D2 variant is associated with early and D3 with delayed CC presentation, whereas A1/2 variant was uniformly distributed between the two age groups.

SUBMITTER: Alfaro A

PROVIDER: S-EPMC5201311 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Different Association of Human Papillomavirus 16 Variants with Early and Late Presentation of Cervical Cancer.

Alfaro Ana A Juárez-Torres Eligia E Medina-Martínez Ingrid I Mateos-Guerrero Norma N Bautista-Huerta Maura M Román-Bassaure Edgar E Villegas-Sepúlveda Nicolás N Berumen Jaime J

PloS one 20161230 12

The median age of cervical cancer (CC) presentation coincides with the mean age of menopause presentation (49 years) in Mexico. Here, we investigated the association between different HPV16 variants and early (≤ 49 years) or delayed (≥ 50 years) CC presentation. We conducted a case-case study that included 462 CCs, 386 squamous cell carcinomas (SCC), 63 adenocarcinomas (ACC), and 13 additional cell types. Variants were identified by PCR and DNA sequencing. The risk conferred by each variant for ...[more]

PMID: 28036379

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Project description:HPV 16 is the cause of cervical carcinoma, but only a small fraction of women with HPV infection progress to this pathology. Besides persistent infection and HPV integration, several studies have suggested that HPV intratype variants may contribute to the development of cancer. The purpose of this study was to investigate the nucleotide variability and phylogenetically classify HPV 16 E6 variants circulating over a period of 16 years in women from Southern Mexico, and to analyze its association with precursor lesions and cervical carcinoma.This study was conducted in 330 cervical DNA samples with HPV 16 from women who were residents of the State of Guerrero, located in Southern Mexico. According of cytological and/or histological diagnosis, samples were divided into the following four groups: no intraepithelial lesion (n?=?97), low-grade squamous intraepithelial lesion (n?=?123), high-grade squamous intraepithelial lesion (n?=?19) and cervical carcinoma (n?=?91). HPV 16 E6 gene was amplified, sequenced and aligned with reference sequence (HPV 16R) and a phylogenetic tree was constructed to identify and classify HPV 16 variants. Chi squared was used and data analysis and statistics were done with SPSS Statistics and STATA softwares.Twenty seven HPV 16 E6 variants were detected in women from Southern Mexico, 82.12% belonged to the EUR, 17.58% to AA1 and 0.3% to Afr2a sublineages. The most common was E-G350 (40%), followed by E-prototype (13.03%), E-C188/G350 (11.82%), AA-a (10.61%), AA-c (6.07%) and E-A176/G350 (5.15%). Eight new E6 variants were found and 2 of them lead to amino acid change: E-C183/G350 (I27T) and E-C306/G350 (K68T). The HPV 16 variant that showed the greatest risk of leading to the development of CC was AA-a (OR?=?69.01, CI?=?7.57-628.96), followed by E-A176/G350 (OR?=?39.82, CI?=?4.11-386.04), AA-c (OR?=?21.16, CI 2.59-172.56), E-G350 (OR?=?13.25, CI?=?2.02-87.12) and E-C188/G350 (OR?=?10.48, CI?=?1.39-78.92).The variants more frequently found in women with cervical carcinoma are E-G350, AA-a, AA-c, E-C188/G350 and E-A176/G350. All of them are associated with the development of cervical carcinoma, however, AA-a showed the highest association. This study reinforces the proposal that HPV 16 AA-a is an oncogenic risk for cervical carcinoma progression in Mexico.

Project description: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.

Project description:BackgroundThe variation of human papillomavirus (HPV) genes or HPV variants demonstrates different risks of cervical cancer. Mutation in the long control region (LCR) at YY1-motifs is one of the mechanisms for enhancing viral oncogene expression during the course of cancer cell progression. In Thai women, cervical cancers are almost always associated with HPV16 variant sub-lineage Asian (HPV16As); however, the mechanism involved remains elusive. The aim of this study was to understand further the oncogenic potential of HPV16As.MethodsA total of 82 HPV16-positive specimens from Thai women were selected from formalin-fixed paraffin-embedded cervical tissues, and the full length E6 gene of each specimen was amplified and sequenced. LCRs of the HPV16As-positive cases were amplified and sequenced to analyze their polymorphisms. Transcriptional activities of the HPV16As LCRs were then compared with sub-lineage European (EUR), sub-lineage Asian-American 1 (AA1) and HPV16 prototype by insertion of the LCRs into the pGL3-Basic vector.ResultsThe HPV16 DNA sequences were classified as HPV16 prototype (18.3%), Asian (As, 61%), Asian American-1 (AA1, 8.5%), European (EUR, 7.3%), Asian African-2 (AFR2, 3.7%) and Java-135C (J135C, 1.2%). The prevalence of HPV16As was 30% in low-grade squamous intraepithelial lesion (LSIL), while that in high-grade squamous intraepithelial lesion (HSIL) and squamous cell cervical carcinoma (SCC) were 63.9% and 66.7%, respectively, which demonstrates a significant association of HPV16As with the disease severity. LCR polymorphisms from 43 HPV16As positive cases were analyzed by PCR-sequencing. Thirty-eight nucleotide variation positions spanned nucleotide positions 7157-82. Ten new mutations found in the HPV16As LCRs were located predominantly at the enhancer and proximal to the 3'-end of the early promoter. The LCRs of the common HPV16As, EUR and AA1 showed 5, 13 and 23-fold higher activity than the HPV16 prototype LCR, while those of the new nucleotide variations of As showed 19 (As-sv1) and 30 (As-sv14) -fold higher activity than the HPV16 prototype.ConclusionsHPV16As DNA sequence variation, especially at the proximal to early promoter in the LCR, enhances transcriptional activity. This could be one of the possible mechanisms for HPV16As-associated cervical cancer development.

Dataset Information

Different Association of Human Papillomavirus 16 Variants with Early and Late Presentation of Cervical Cancer.

Publications

Different Association of Human Papillomavirus 16 Variants with Early and Late Presentation of Cervical Cancer.

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