RESUMO
OBJECTIVES: In this study, we sought to correlate genotype test results for human papillomavirus (HPV) types 16, 18, and 45 with histopathologic follow-up diagnoses in patients with messenger RNA (mRNA) high-risk HPV-positive, cytology-negative results. METHODS: We identified 1,157 patients with mRNA HPV-positive, cytology-negative cervical screening test results between June 2015 and June 2018. Reflex HPV 16/18/45 genotype results were documented in 1,018 women aged 30 years or older, 318 of whom had follow-up within 18 months. RESULTS: Histopathologic findings of cervical intraepithelial neoplasia 2 or worse (CIN2+) were diagnosed in 14 of 122 (11.5%) patients positive for HPV 16/18/45 vs in seven of 196 (3.6%) HPV 16/18/45-negative patients. Three patients with high-risk HPV-positive, cytology-negative cervical screening test results were diagnosed with stage I cervical adenocarcinomas following early colposcopic referral and biopsy after HPV 16/18/45-positive genotype results. CONCLUSIONS: Immediate reflex HPV 16/18/45 genotyping of mRNA HPV-positive, cytology-negative patients led to early colposcopic referral and histopathologic diagnoses of three difficult-to-detect, low-stage, cervical adenocarcinomas and significantly increased overall early detection of CIN2+ lesions.
Assuntos
Detecção Precoce de Câncer , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , RNA Mensageiro/análise , Displasia do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Genótipo , Papillomavirus Humano 16/classificação , Papillomavirus Humano 18/classificação , Humanos , Pessoa de Meia-Idade , Neoplasias do Colo do Útero/virologia , Displasia do Colo do Útero/virologiaRESUMO
Persistent infections with high-risk human papillomaviruses (HR-HPVs) are linked to the development of cervical cancer due to a deregulation of the productive viral cycle in the host cell, leading to cell transformation. The E2 viral protein is expressed early during an HPV infection and regulates viral replication and transcription. Other functions have been attributed to E2, such as the promotion of apoptosis that are independent of its role in the regulation of the expression of E6 and E7 viral oncogenes. Moreover, it has been shown that the HPV16 E2 protein has regulatory effects on cellular gene expression, suggesting that it participates in the modulation of different cellular processes. Intratype genomic variations within high-risk HPV types have an impact on the prognosis of HPV-related lesions. Nevertheless, the biological significance of HPV18 E2 intratype variations has not been analysed previously. The aim of this study was to determine whether HPV18 E2 intratype variations differentially modulate gene expression and whether cell-death-related genes are affected by variations in E2. We demonstrate that HPV18 E2 intratype Asian Amerindian (AsAi) and African (Af) variants differentially affect gene expression profiles. Although the E2-AsAi variant was found to modulate a larger number of cellular genes, both E2 variants affected similar cellular processes. Nevertheless, E2-AsAi and E2-Af variants showed differences in their ability to induce apoptosis, where E2-Af had a stronger effect. The differences in gene expression profiles in cells harbouring E2 intratype variants suggest a possible effect on diverse cellular signalling pathways, and this might suggest an approach for identifying biological processes regulated by HPV18 E2 intratype variants.
Assuntos
Apoptose/genética , Proliferação de Células/genética , Regulação da Expressão Gênica/genética , Papillomavirus Humano 18/genética , Proteínas Oncogênicas Virais/genética , Linhagem Celular Tumoral , Feminino , Expressão Gênica/genética , Perfilação da Expressão Gênica , Células HEK293 , Papillomavirus Humano 18/classificação , Humanos , Células MCF-7 , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/virologiaRESUMO
HPV types 16 and 18 were studied in paraffin-fixed cervical biopsy collected in southern Brazil. HPV 16, HPV 18 and co-infection HPV 16/18 were identified in 10/57 (17.5%), 4/57 (7%) and in 43/57 (75.4%) samples, respectively. Southern Brazil has one of the highest prevalence rates of HPV 16/18 reported.
Assuntos
Colo do Útero/patologia , Coinfecção/virologia , Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 18/isolamento & purificação , Infecções por Papillomavirus/virologia , Adolescente , Adulto , Biópsia , Brasil/epidemiologia , Colo do Útero/virologia , Coinfecção/epidemiologia , Coinfecção/patologia , Feminino , Papillomavirus Humano 16/classificação , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/classificação , Papillomavirus Humano 18/genética , Humanos , Pessoa de Meia-Idade , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/patologia , Prevalência , Adulto JovemRESUMO
ABSTRACT HPV types 16 and 18 were studied in paraffin-fixed cervical biopsy collected in southern Brazil. HPV 16, HPV 18 and co-infection HPV 16/18 were identified in 10/57 (17.5%), 4/57 (7%) and in 43/57 (75.4%) samples, respectively. Southern Brazil has one of the highest prevalence rates of HPV 16/18 reported.
Assuntos
Humanos , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Colo do Útero/patologia , Infecções por Papillomavirus/virologia , Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 18/isolamento & purificação , Coinfecção/virologia , Biópsia , Brasil/epidemiologia , Colo do Útero/virologia , Prevalência , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/epidemiologia , Papillomavirus Humano 16/classificação , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/classificação , Papillomavirus Humano 18/genética , Coinfecção/patologia , Coinfecção/epidemiologiaRESUMO
Cervical cancer is the fourth most common cancer among women, and â¼70-80% of these cancers are associated with two human papillomavirus types: HPV16 and HPV18. Several studies have reported that intra-type diversity is associated with the progression of infection to invasive cancer. Herein, we report the genetic diversity of HPV16 and HPV18 in a cohort of 594 Brazilian women with invasive cervical cancer and describe the prevalence of lineages and intra-type diversity prior to the implementation of the public immunization program in Brazil. HPV detection and genotyping were performed using PCR, PGMY/GP primers, and DNA extracted from fresh tumors. The HPV16 (378 women) and HPV18 (80 women) lineages were identified by PCR and sequencing of the LCR and E6 fragments, followed by SNV comparison and phylogenetic analysis. In our cohort, was found a higher frequency of the lineage A (in 217 women), followed by lineage D (in 97 women) and lineages B and C (in 10 women each) for HPV16; and a higher frequency of lineage A (in 56 women) followed by lineage B (in 15 women) in HPV18. The genetic diversity of HPV16 indicated a recent expansion of specific variants or a selective advantage that is associated with invasive cancer; this pattern was not observed for HPV18.
Assuntos
Variação Genética , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Neoplasias do Colo do Útero/virologia , Adulto , Idoso , Brasil/epidemiologia , DNA Viral/genética , Proteínas de Ligação a DNA/genética , Feminino , Genoma Viral , Genótipo , Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 18/classificação , Papillomavirus Humano 18/isolamento & purificação , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas Oncogênicas Virais/genética , Filogenia , Prevalência , Proteínas Repressoras/genética , Fatores de Risco , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/patologia , Adulto JovemRESUMO
Contribution over time of human papillomavirus (HPV) types in human cancers has been poorly documented. Such data is fundamental to measure current HPV vaccines impact in the years to come. We estimated the HPV type-specific distribution in a large international series of invasive cervical cancer (ICC) over 70 years prior to vaccination. Paraffin embedded ICC cases diagnosed between 1940 and 2007 were retrieved from eleven countries in Central-South America, Asia and Europe. Included countries reported to have low-medium cervical cancer screening uptake. Information on age at and year of diagnosis was collected from medical records. After histological confirmation, HPV DNA detection was performed by SPF-10/DEIA/LiPA25 (version1). Logistic regression models were used for estimating the adjusted relative contributions (RC) of HPV16 and of HPV18 over time. Among 4,771 HPV DNA positive ICC cases, HPV16 and HPV18 were the two most common HPVs in all the decades with no statistically significant variations of their adjusted-RC from 1940-59 to 2000-07 (HPV16-from 61.5 to 62.1%, and HPV18-from 6.9 to 7.2%). As well, the RC of other HPV types did not varied over time. In the stratified analysis by histology, HPV16 adjusted-RC significantly increased across decades in adenocarcinomas. Regarding age, cases associated to either HPV16, 18 or 45 were younger than those with other HPV types in all the evaluated decades. The observed stability on the HPV type distribution predicts a high and stable impact of HPV vaccination in reducing the cervical cancer burden in future vaccinated generations.
Assuntos
Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Invasividade Neoplásica/genética , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/patologia , Adulto , Idoso , Ásia , América Central , DNA Viral/genética , DNA Viral/isolamento & purificação , Detecção Precoce de Câncer , Europa (Continente) , Feminino , Papillomavirus Humano 16/classificação , Papillomavirus Humano 16/patogenicidade , Papillomavirus Humano 18/classificação , Papillomavirus Humano 18/patogenicidade , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Inclusão em Parafina , Estudos Retrospectivos , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologiaRESUMO
BACKGROUND: Seropositivity to human papillomavirus (HPV)16 and 18 antibodies is used as a measure of cumulative HPV exposure and as a stratifier of HPV exposure for vaccine efficacy analyses. Overall performance of these assays, as a measure of HPV exposure, has not been evaluated. METHODS: Using data from the enrollment phase of the HPV16/18 vaccine trial in Costa Rica, we evaluated the performance of the polyclonal enzyme-linked immunosorbent assay (ELISA) HPV16 and 18 serological assays as a measure of HPV exposure. Biologic (e.g., HPV infection at the cervix) and behavioral characteristics (e.g., lifetime number of sexual partners) with known associations with current and past HPV infection were used to define cases and controls (HPV exposed vs. not exposed). Prevaccination serum was measured for antibodies against HPV16 and 18 by ELISA; cervical samples were tested for HPV DNA using PCR SPF10/LiPA25. ELISA results were analyzed using receiver-operator characteristic curves; performance was evaluated at the manufacturer set cut point (HPV16 = 8, HPV18 = 7) and at cut points chosen to optimize sensitivity and specificity (HPV16 = 34, HPV18 = 60). RESULTS: Defining cases as type-specific HPV DNA positive with high-grade abnormal cytology (i.e., combined molecular and microscopic markers of infection), HPV16-ELISA gave sensitivity that was lower at the optimal cut point than the manufacturer cut point (62.2 compared with 75.7, respectively; P = 0.44). However, specificity was higher (85.3 compared with 70.4, respectively; P < 0.0001). Similarly, HPV18-ELISA gave sensitivity that was lower at the optimal cut point than the manufacturer cut point (34.5 compared with 51.7, respectively; P = 0.40), with higher specificities (94.9 compared with 72.6, respectively; P < 0.0001). CONCLUSIONS: Modifying cut points did not improve the low sensitivity. The low sensitivity of this assay does not support its use for risk stratification or clinical settings.
Assuntos
Anticorpos Antivirais/sangue , Ensaio de Imunoadsorção Enzimática/normas , Papillomaviridae/imunologia , Infecções por Papillomavirus/imunologia , Biomarcadores , Intervalos de Confiança , Costa Rica , DNA Viral/isolamento & purificação , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Papillomavirus Humano 16/classificação , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/classificação , Papillomavirus Humano 18/genética , Papillomavirus Humano 18/imunologia , Humanos , Análise Multivariada , Papillomaviridae/classificação , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus , Reação em Cadeia da Polimerase , Sensibilidade e Especificidade , Adulto JovemRESUMO
HPV-18 is the second most prevalent human papillomavirus genotype found in cervical cancer. Nucleotide variations in HPV-18 sequence can interfere with the viral oncogenic potential. However, the knowledge about HPV-18 variants in Brazil is still limited. The present study aims to determine the LCR, E6, and L1 genetic variability of HPV-18 variants found in women co-infected with HIV-1 in Central Brazil. Four HPV-18 samples were identified and had the LCR, E6, and L1 genomic regions sequenced. It was possible to characterize three European variants and one African variant of HPV-18. All of them are new variants, showing nucleotide substitutions not previously reported. Nucleotide variations in binding sites for transcriptional factors were observed. Phylogenetic analysis was also performed, evidencing the three clusters related to the Asian-American, African, and European variants. The characterization of HPV genetic variability is of pivotal importance to the understanding of the viral pathogenicity.