L’accouchement prématuré a été récemment associé à la persistance du virus du papillome humain de type 16 (VPH-16) en grossesse. Il demeure toutefois difficile de savoir si cette association est causale et d’en expliquer les mécanismes biologiques potentiels. Afin de mieux caractériser cette association, nous avons étudié l'association entre la charge virale du VPH-16 en grossesse et l’accouchement prématuré. Les données de 48 femmes enceintes qui étaient positives pour le VPH-16 dans la cohorte HERITAGE ont été analysées avec un modèle de régression logistique, où la confusion a été ajustée avec scores de propension et pondération par l’inverse de probabilité de traitement. La charge virale du VPH, mesurée avec test PCR en nombre de copies/cellule au 1er et 3ième trimestre de grossesse, a été analysée en continue et dichotomisée à l’aide de différents seuils (0,5, 1,0 et 2,0). La charge virale (en continue) au 1er trimestre de grossesse a été associée à l’accouchement prématuré avec un OR ajusté (aOR) de 1,13 [IC 95% 1,03-1,25]. Le aOR pour la charge virale catégorisée avec seuil de 1,0 copie/cellule au 1er trimestre était de 15,03 [IC 95 % 1,75- 129,26]. Les analyses avec des seuils différents et au 3ième trimestre de grossesse ont données des résultats similaires quoique les ORs n’étaient pas toujours statistiquement significatifs. Nos résultats suggèrent une forte association entre la charge virale du VPH-16 et l’accouchement prématuré. Cette étude contribue à une meilleure compréhension des mécanismes tout en supportant la causalité. / Preterm birth has recently been associated with the persistence of human papillomavirus 16 (HPV-16) during pregnancy. However, it remains difficult to determine whether this association is causal and to explain its potential biological mechanisms. To better characterize this association, we investigated the association between HPV-16 viral load during pregnancy and preterm birth. Data from 48 pregnant women positive with HPV-16 infection from the HERITAGE cohort were analyzed using a logistic regression model, where confounders were adjusted with propensity scores and inverse probability treatment weighting. HPV viral load, measured with a PCR test as copy numbers/cell during the 1st and 3rd trimester of pregnancy was analyzed continuously, and categorized using different cutoffs (0.5, 1.0 and 2.0). Continuous viral load at 1st trimester of pregnancy was associated with preterm birth with an adjusted OR (aOR) of 1.13 [95% CI: 1.03-1.25]. The aOR viral load categorized with cutoff 1 copy/cell at 1st trimester was 15.03 [1.75-129.26]. Analyses with different cutoffs in 3rd trimester of pregnancy gave similar results although the ORs were not always statistically significant. Our results suggest a strong association between HPV-16 viral load and preterm birth. This study contributes to a better understanding of the mechanisms and provides an additional argument on causality.

Background. Head and neck cancers (HNC) are among the most common malignancies worldwide, and about 90–92% of oral neoplasias are oral squamous cell carcinomas (OSCC). Alcohol and tobacco consumption have been recognized as the main risk factors for OSCC development. Oncogenic viruses, such as human papillomavirus (HPV) or Epstein-Barr virus (EBV), as well as genetic alterations may also contribute to tumour formation.  Aims. To study the prevalence of HPV, EBV, Herpes simplex type-1 (HSV-1), and HPV-16 and their integration status as well as the molecular mechanisms that can serve as a basis for the development of OSCC. Results. In Paper I we reported a statistically significant increase in the prevalence of HPV-16 in oral epithelial dysplasia (OED) and OSCC samples compared to controls. A statistically significant increase was also seen in integrated HPV-16 compared to episomal viral forms when comparing OED and OSCC samples. Paper II reported the detection of HSV-1 in 54% of healthy samples, in 36% of oral leukoplakia samples, and 52% of OSCC samples. However, these differences were not statistically significant. In Paper III we reported a statistically significant increase in the detection of HPV-positive samples when comparing nested polymerase chain reaction (PCR) with single-PCR results in OSCC and fresh oral mucosa. Paper IV reported that the highest prevalence of HPV (65%) was seen in Sudan, while an HSV-1 prevalence of 55% and an EBV prevalence of 80% were seen in the UK. Finally, Paper V reported that the mRNA levels of Bcl-2, keratin 1, keratin 13, and p53 were significantly lower and that the level of survivin was significantly higher in the OSCC samples of the toombak users than in their paired control samples. Significant downregulation in keratin 1 and keratin 13 expression levels was found in the OSCC samples of the non-toombak users relative to their normal control samples. Conclusion. HPV-16 integration was increased in oral epithelial dysplasia and OSCC compared to normal oral mucosa. Nested PCR is a more accurate method of establishing HPV prevalence in samples containing low copy numbers of HPV DNA. HPV and EBV may be a risk factor in OSCC development. Our findings confirmed the role of survivin in OSCC carcinogenesis and survivin might be interesting as a biomarker to be monitored. The results presented here provide both clinical and biological insights that will bring us closer to the goal of managing this disease and improving treatment and outcomes for future patients.

Orientador: Regina Helena Garcia Martins / Resumo: Mercuri G. Incidência e Prevalência da Papilomatose Laríngea no Estado de São Paulo [dissertação]. Botucatu, SP: Faculdade de Medicina de Botucatu, Universidade Estadual Paulista; 2019. Introdução: A papilomatose respiratória recorrente ou papilomatose laríngea recorrente é a neoplasia benigna da laringe causada pelo Papiloma Vírus Humano, caracterizando-se pela presença de lesões proliferativas exofíticas recorrentes. A ausência de tratamento curativo, os custos relacionados ao diagnóstico, prevenção e tratamento das doenças causadas pelo HPV apresentam importante impacto econômico em todo mundo. No entanto, a falta de dados epidemiológicos nacionais, quanto à incidência e prevalência da papilomatose laríngea no Brasil não nos permite analisar o comportamento da doença em nossa população, bem como os benefícios da vacinação. Objetivo: Estimar a incidência e a prevalência da Papilomatose Laríngea no Estado de São Paulo. Métodos: Estudo populacional que objetivou levantar todos os casos diagnosticados de Papilomatose Laríngea do Estado de São Paulo, considerando os principais centros de diagnóstico desta enfermidade. Foram mapeados e selecionados os principais serviços de residência e especialização em Otorrinolaringologia do Estado de São Paulo, a partir dos dados fornecidos pela Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial (ABORL-CCF). Através do preenchimento de um questionário obtivemos os dados para estimar a prevalência e a incidência mínimas p... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Mercuri G. Incidence and Prevalence of Laryngeal Papillomatosis in São Paulo State [thesis]. Botucatu, SP: Faculty of Medicine of Botucatu, Universidade Estadual Paulista; 2019. Introduction: Recurrent respiratory papillomatosis or recurrent laryngeal papillomatosis is a benign laryngeal neoplasm caused by Human Papilloma Virus, characterized by the presence of recurrent exophytic proliferative lesions. Without curative treatment, costs related to the diagnosis, prevention, and treatment of HPV-related diseases have a significant economic impact worldwide. However, the lack of national epidemiological data on the incidence and prevalence of laryngeal papillomatosis in Brazil does not allow us to analyze the behavior of the disease in our population, as well as the benefits of vaccination. Objective: To estimate the incidence and prevalence of Laryngeal Papillomatosis in the State of São Paulo. Methods: A population study was conducted aiming to raise all the diagnosed cases of Laryngeal Papillomatosis of the State of São Paulo, considering the main centers of diagnosis of this disease. The main services of residence and specialization in Otorhinolaryngology of the State of São Paulo were mapped and selected, based on the data provided by the Brazilian Association of Otorhinolaryngology and Cervical-Facial Surgery (ABORL-CCF). By completing a questionnaire we obtained the data to estimate the minimum prevalence and incidence for the State in 2017. Results: The questionnaire wa... (Complete abstract click electronic access below) / Mestre

Submitted by Mariana Dornelles Vargas (marianadv) on 2015-05-29T17:36:45Z No. of bitstreams: 1 percepcao_sobre.pdf: 624117 bytes, checksum: 32c35c4fe3164fc8bd6f5aca246544df (MD5) / Made available in DSpace on 2015-05-29T17:36:45Z (GMT). No. of bitstreams: 1 percepcao_sobre.pdf: 624117 bytes, checksum: 32c35c4fe3164fc8bd6f5aca246544df (MD5) Previous issue date: 2012-05 / Nenhuma / Esta dissertação é composta por dois artigos, o primeiro deles de revisão sistemática da literatura e o segundo um artigo empírico. No estudo 1, buscou-se realizar uma revisão sistemática da literatura internacional sobre percepção da doença e o câncer. Foram encontrados 11 artigos. Os resultados mostraram que os estudos são diversos e o foco das pesquisas é abrangente, relacionando a percepção sobre a doença e o câncer em diversas situações, especialmente na qualidade de vida. No estudo 2, o objetivo foi avaliar e comparar as percepções sobre o câncer do colo do útero em três grupos de mulheres: 1) mulheres com diagnóstico de câncer do colo do útero e em tratamento para a doença; 2) mulheres com lesões precursoras de câncer uterino ou contaminadas pelo HPV; e 3) mulheres sem a doença e sem lesão precursora. Participaram da pesquisa 150 mulheres adultas em atendimento ambulatorial de ginecologia e ambulatório de oncologia em dois hospitais de Porto Alegre (RS). Foram utilizadas como instrumentos a ficha de Dados Sociodemográficos e Clínicos, o Questionário de percepção sobre a doença Revised Illness Perception Questionnaire (IPQ-R) e Revised Illness Perception Questionnaire for Healthy People (IPQ-RH). Os resultados mostraram diferenças na percepção entre os grupos nas dimensões identidade (F=11,654, p<0,001), duração cíclica da doença (F=4,416, p<0,05) e causas da doença (F=15,941; p<0,001), o que mostra que as mulheres saudáveis apresentaram percepções positivas em relação à doença, diferente das mulheres com lesão e com câncer. As percepções entre os três grupos se assemelharam nas seguintes dimensões: duração da doença (aguda/crônica), consequência da doença, controle pessoal e do tratamento, coerência da doença e representações emocionais. / This dissertation consists of two articles, the first one being a systematic review of the literature and the second an empirical study. In study 1, it sought to conduct a systematic review of international literature regarding the perception of the disease and the cancer itself. 11 articles were found. The results showed that the studies are diverse and the focus of research is comprehensive, listing the perception about the disease and the cancer in various situations, especially in terms of quality of life. In study 2, the objective was to evaluate and compare the perceptions about cervical cancer found in three groups of women: 1) women diagnosed with cervical cancer and undergoing treatment for the disease; 2) women with uterine early stage cancer lesions or with HPV infections; and 3) women not having the disease nor the early stage cancer lesions. 150 adult women participated in the study at clinical gynecology and oncology outpatient clinics in two hospitals in Porto Alegre (RS). as instruments, the Demographic and clinical data sheet, the Questionnaire of perception about the disease Revised Illness Perception Questionnaire (IPQ-R) and Revised Illness Perception Questionnaire for Healthy People (IPQ-RH) were used. The results showed differences in perception between the groups in the identity dimensions (F = p < 0.001 11.654,), cyclic duration of disease (F = 4.416, p < 0.05) and causes of disease (F = 15.941, p < 0.001), which shows that healthy women showed positive perceptions in relation to disease, different from women with cancer and lesions. Perceptions among the three groups resembled each other in the following dimensions: length of the disease (acute/chronic), as a result of illness, personal control and consistency of treatment, disease and emotional representations.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Cervical cancer is the second most common cancer among women worldwide and one of the most prevalent female cancers in Brazil. In premalignant and malignant lesions of the uterine cervix the p16INK4a protein, which participates in cell cycle control, exhibits a dramatic increase in its expression possibly due to the presence of human papillomavirus (HPV) oncoproteins. Two polymorphisms in the p16 gene, p16INK4a 540C>G and p16 580C> T, are located in the 3' untranslated region (3'UTR), which is involved in the post-transcriptional regulation of gene expression. The aim of this study was to investigate possible associations between the p16 500C>G and p16 540C>T polymorphisms and the developing of cervical neoplasias and/or lesion severity, considering the expression levels of the p16INK4a protein in cervical lesions, and some classic risk factors for cervical cancer, including HPV infection. A total of 567 women residents in Rio de Janeiro was selected, 319 with abnormal cervical cytology results (case group), and 248 with no previous history of cervical cytological changes (comparison group). Peripheral blood samples from all participants were used for molecular analysis of the polymorphisms p16 500C>G and p16 540C>T, which was performed by PCR-RFLP (polymerase chain reaction - restriction fragment length polymorphism) using the restriction enzymes MspI and HaeIII, respectively. The expression of p16 in 137 biopsies of women belonging to the group of cases was assessed by immunohistochemistry. The detection of HPV DNA in cervical cells was performed in all samples of the comparison group and in 194 samples of the case group by a PCR-based method using two primers pairs, MY09/MY11 and GP05+/GP06+. TheINK4a two study groups are in Hardy-Weinberg equilibrium. The genotype distributions for p16 500C>G and p16 540C>T and the distributions of haplotype combinations in the two groups were not statistically different. The analysis of the subgroup HSIL+cancer (cases with high-grade intraepithelial lesion or invasive carcinoma) compared to the subgroup HSIL (cases with low-grade squamous intraepithelial lesions) revealed a significant difference in the distribution of haplotype combinations (p = 0.036) and marginal differences in the genotype distributions for p16 500C>G (p = 0.071) and p16 540C>T (p = 0.051). The p16 540G allele, in heterozygosis or homozygosis (OR = 1.91, 95% CI = 1.08-3.37), and the haplotype combination p16 500C-540C 500G-540C (OR = 2.34, 95% CI = 1.202-4.555) showed to be associated with the severity of cervical lesions. On the other hand the p16 580T/T genotype (OR = 0.25, 95% CI = 0.08-0.79), and the haplotype combination p16 500C-540T 500C-540T (OR=0.27, 95% CI = 0.088-0.827) exhibited a protective effect against the development of higher grade cervical lesions. Interaction analyses between the p16 polymorphisms and the p16 protein expression or the HPV infection were compromised by the reduced number of analyzed samples. No interaction was observed between the studied polymorphisms and the classical risk factor for cervical cancer. Our data point out the importance of the p16 gene polymorphisms as severity markers in cervical neoplasia. INK4aINK4aINK4a. / O câncer de colo do útero é o segundo carcinoma mais frequente em mulheres no mundo e um dos cânceres femininos mais incidentes no Brasil. Em lesões pré-malignas e malignas do colo uterino, a proteína p16INK4a, que participa do controle do ciclo celular, apresenta um aumento considerável de sua expressão, devido possivelmente à presença de oncoproteínas do papilomavírus humano (HPV). Dois polimorfismos no gene p16INK4a, p16 500C>G e p16 540C>T, estão localizados na região 3 não traduzida (3UTR), que está envolvida na regulação pós-transcricional da expressão gênica. O objetivo deste estudo foi avaliar possíveis associações entre os polimorfismos p16 500C>G e p16 540C>T e o desenvolvimento de neoplasias cervicais e/ou a severidade das lesões, considerando os níveis de expressão da proteína p16INK4a nas lesões cervicais e certos fatores de risco clássicos para o câncer cervical, incluindo a infecção pelo HPV. Para isso, foram selecionadas 567 mulheres residentes no Rio de Janeiro, 319 com citologia cervical alterada (grupo de casos) e 248 sem história prévia de alteração citológica do colo uterino (grupo de comparação). Amostras de sangue periférico de todas as participantes foram utilizadas na análise molecular dos polimorfismos p16 500C>G e p16 540C>T através da técnica de PCR-RFLP (reação em cadeia da polimerase - polimorfismo de comprimento de fragmento de restrição), usando as enzimas de restrição MspI e HaeIII, respectivamente. A expressão da proteína p16INK4a em 137 biópsias de mulheres pertencentes ao grupo de casos foi avaliada por imunohistoquímica. A detecção de DNA do HPV em células cervicais foi feita em todas as amostras do grupo de comparação e em 194 amostras do grupo de casos pela técnica de PCR, usando dois pares de oligonucleotídeos, MY09/MY11 e GP05+/GP06+. Os dois grupos de estudo se encontram em equilíbrio de Hardy-Weinberg. As distribuições genotípicas para p16 500C>G e p16 540C>T e as distribuições de combinações haplotípicas nos dois grupos não apresentaram diferenças significativas. A análise do subgrupo HSIL+câncer (casos com lesão intraepitelial de alto grau ou carcinoma invasivo) em comparação com o subgrupo LSIL (casos com lesão intraepitelial de baixo grau) revelou diferença significativa entre as distribuições das combinações haplotípicas (p = 0,036) e diferenças marginais entre as distribuições genotípicas para p16 500C>G (p = 0,071) e p16 540C>T (p = 0,051). O alelo p16 540G, em heterozigose ou homozigose (OR = 1,91, IC 95% = 1,08-3,37), e a combinação haplotípica p16 500C-540C 500G-540C (OR = 2,34, IC 95% = 1,202-4,555) mostraram-se associados com a severidade da lesões cervicais. Já o genótipo p16 540T/T (OR = 0,25, IC 95% = 0,08-0,79), e a combinação haplotípica p16 500C-540T 500C-540T (OR = 0,27, IC 95% = 0,088-0,827) exibiram papel protetor contra o desenvolvimento de lesões mais severas. As análises de interação entre os polimorfismos de p16INK4a e a expressão de p16 ou a infecção pelo HPV foram comprometidas pelo número reduzido de amostras analisadas. Não se observou qualquer interação entre os polimorfismos estudados e os fatores de risco clássicos para o câncer de colo uterino. Nossos resultados apontam para a importância dos polimorfismos do gene p16INK4a como marcadores de severidade da neoplasia cervical.

Submitted by Edisangela Bastos (edisangela@ufpa.br) on 2017-01-26T11:54:45Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_AspectosClinicosEpidemiologicos.pdf: 1449412 bytes, checksum: 578476d05f286ad66ccb88c9b265d702 (MD5) / Approved for entry into archive by Edisangela Bastos (edisangela@ufpa.br) on 2017-01-26T11:55:15Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_AspectosClinicosEpidemiologicos.pdf: 1449412 bytes, checksum: 578476d05f286ad66ccb88c9b265d702 (MD5) / Made available in DSpace on 2017-01-26T11:55:16Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_AspectosClinicosEpidemiologicos.pdf: 1449412 bytes, checksum: 578476d05f286ad66ccb88c9b265d702 (MD5) Previous issue date: 2013 / O papiloma vírus humano (HPV) é um vírus que infecta a pele e a mucosa. Está associado ao câncer do colo do útero, por aumentar a probabilidade deste acontecer, mas paralelo a este, outros fatores comportamentais de risco devem ser averiguados. Tendo como foco a investigação da prevalência e os aspectos clínicos epidemiológicos da infecção genital pelo HPV em mulheres de população Urbana e Ribeirinha do município de Santarém-Pará, foi realizado um estudo comparativo, observacional, descritivo e analítico, do tipo transversal, onde houve a seleção de 511 mulheres, sendo 391 mulheres da população Urbana (38,54 ± 11,4 anos de idade) e 120 da população Ribeirinha (37,2 ± 11,7 anos de idade). Para a coleta de dados, realizou-se uma entrevista contendo informações acerca dos fatores que podem estar associados à prevalência de HPV e câncer cervical, além de uma coleta de material biológico que foi analisado através da citologia oncótica, isolamento do DNA e PCR. A tabulação dos dados foi realizada no programa Excel e a análise estatística no aplicativo Bioestat 5.0®. Verificou-se uma baixa prevalência do HPV, comparando-se com resultados de pesquisas de outras regiões. Notou-se homogeneidade dos resultados das mulheres de ambas as populações, divergindo apenas nos tópicos escolaridade, tabagismo atual, número de parceiros sexuais durante a vida e uso de anticoncepcional oral durante a vida. Conclui-se que, apesar da localização geográfica, não há para o município de Santarém uma grande mudança no perfil das mulheres entre dados encontrados na população urbana e na população ribeirinha quanto à epidemiologia do HPV. / The human papilloma virus (HPV) is a virus that infects the skin and mucosa and is associated with cancer of the cervix, by increasing the likelihood of this happening, but parallel to this, other behavioral risk factors should be investigated. Focusing research on the prevalence and the clinical epidemiology of genital infection by HPV in women of urban and riverside municipality of Santarém-Para State proposed a comparative study to be observational, descriptive and analytical , transversal, where there was a selection of 511 women, with 391 women (38.54 ± 11.4 years) and 120 for Urban sample comprised the sample riverfront (37.2 ± 11.7 years). For data collection an interview was conducted, containing information about the factors that may be associated with the incidence of HPV and cervical cancer, plus a collection of biological material that was analyzed by cytology, DNA isolation and PCR . The analysis of these data was performed using the tab in excel and subsequent treatment through statistical software Bioestat 5.0, with the results a low prevalence of HPV compared with surveys from other regions, and homogeneity of results between urban and riverside, differing only in the topics of education, smoking status, number of sexual partners during their lifetime, and oral contraceptive used during life. Concluding that despite geographical location, there is for the municipality of Santarém a big change in the profile of woman between data found in the urban area and the waterfront on the epidemiology of HPV.

Introduction: Oropharyngeal tumours belong to the most common malignancies situated in the head and neck area. In the past, their incidence has been associated with classical risk factors (smoking and alcohol use). In the recent years, the increase of oropharyngeal carcinomas resulting from HPV (human papilloma virus) infection incidence has been observed. The change of their aetiology also implies a number of clinical differences, the most important being a significantly better survival prognosis in patients with HPV+ carcinomas. Aims: The main goal of this thesis was to characterize correctly patients with oropharyngeal carcinomas and to identify different specifics of nursing intensive care for these patients. Methods: The quantitative prospective study involved 30 patients following their surgical treatment of oropharyngeal carcinoma, hospitalised in an intensive care unit. The patients were divided into 3 groups: HPV+ non-smokers, HPV+ smokers, HPV- smokers. Results: The study confirmed the demographic differences between individual patient groups. The HPV+ non-smokers group is characterized by a lower age in average, which is significantly reflected in a reduced duration of hospital stay. In addition, opioid administration rate, infection rates and postoperative complications incidences are...

An association between persistent Human papillomavirus (HPV) infection in women and cervical cancer has been established. Young women are particularly at risk of acquiring sexually transmitted infections such as HPV because of risky sexual activity and physiological immaturity. While at risk though, young women have been shown to be amenable to health promoting initiatives. There are a small number of international studies concerning adolescent HPV infection and the risk factors associated with infection, but there is currently no evidence on the prevalence and risk factors for HPV in an Australian, sexually active female adolescent population. This study aimed to provide evidence of the prevalence of HPV, risk factors associated with infection and the patterns of sexual activity in a female sexually active, senior high school population in the Australian Capital Territory. Participants in this study were a convenience sample of 161 sexually active 16-19 year old females who had an HPV test who were attending a senior high school in the Australian Capital Territory. Nurses and doctors using a clinical record collected information about sexual and other risk behaviours. Self-obtained vaginal swabs were tested for HPV DNA using the polymerase chain reaction method and genotyping was undertaken. The HPV prevalence in this cohort of young women was 1 1.2%. High-risk genotypes were found in 55.5% and multiple genotypes were found in 38.8%. There was a significant association found between HPV infection and having had more than one male partner with whom vaginal intercourse had occurred in the previous six months. No statistically significant association was found between HPV and the age of coitarche, length of time young women had been sexually active, condom use, and smoking or alcohol intake. A young age at coitarche was common for this group. Smoking and alcohol use was seen in large proportions in this group. This is the first Australian study that has examined the prevalence and risk factors for genital HPV in this demographic group. The HPV prevalence is lower than in international studies in comparable groups, in similar age groups and much lower than in older women both in Australia and overseas. With the comparatively low prevalence comes an opportunity for important public health interventions for this group including routine Pap smears, vaccination against the high-risk types of HPV when this becomes available and strategies for young women to reduce their number of male sexual partners. A substantial amount of young women in this study were sexually active aged under 16 years. Whilst this was not identified as being a risk factor in this study, it is both a health and personal safety issue for these young women. There is a demonstrated need for health promotion strategies for this cohort about the consumption of safe levels of alcohol and for smoking cessation. Further research is recommended that includes a repetition of this study with a larger sample, the use of a prospective study design to identify trends in infection and examination of HPV prevalence and risk factors for a variety of populations.

<p>A previous model of morphological pathogenesis assumed that cervical carcinoma is of monoclonal origin and progresses through multiple steps from normal epithelium via CINS into invasive carcinomas. The aim of this study was to investigate the molecular mechanism of pathogenesis of cervical neoplasia. </p><p>In the clonality study, we found that 75% (6/8) of informative cases of cervical carcinoma had identical patterns of loss of heterozygosity (LOH) in the multiple synchronous lesions, while the remaining cases had different LOU patterns. In an extensively studied "golden case", the multiple carcinoma and cervical intraepithelial neoplasia (CIN) lesions could be divided into several different clonal groups by the X-chromosome inactivation patterns, HPV 16 mutations and LOH patterns. The biggest clonal family included one CIN II, one CIN III and four carcinoma samples, while four other monoclonal families of carcinoma did not include CIN lesions. These results suggested that cervical carcinoma can be either monoclonal or polygonal and contains clones developing either directly or via multiple steps. In the study of HPV types and HPV16 variations, the results confirmed that specific HPV types are the cause of cervical carcinoma but failed to support the previous opinion that HPV16 E6 variants are more malignant than the prototype. We established a novel classification called oncogene lineage of HPV16, and found that additional variations of HPV 16 oncogenes might be a weak further risk factor for cervical carcinoma. In the study of LOH, we found that interstitial deletion of two common regions of chromosome 3p, i.e., 3p2l.1-3p2l.3, and 3p22, was an early event in the development of cervical carcinoma. The results showed that the hMLH1 gene, located in 3p22 and showing LOH in 43% of the studied cases, was not involved in the development of cervical carcinoma because neither the expression level of protein nor the gene sequence was altered in these cases. </p><p>In summary, a suggested model of molecular pathogenesis of cervical carcinoma is as follows. Specific types of HPV infect one or more committed stem cells in the basal layer of the epithelium. Fully efficient LOH events turn one (monoclonal origin) or more (polyclonal origin) HPV-infected stem cells into carcinoma cells without CIN steps. Less efficient LOH events would lead to CIN steps where some other unknown factors require to be added to facilitate the formation of carcinoma. In the absence of LOH events no carcinoma develops from the HPV-infected stem cells.</p>

A previous model of morphological pathogenesis assumed that cervical carcinoma is of monoclonal origin and progresses through multiple steps from normal epithelium via CINS into invasive carcinomas. The aim of this study was to investigate the molecular mechanism of pathogenesis of cervical neoplasia. In the clonality study, we found that 75% (6/8) of informative cases of cervical carcinoma had identical patterns of loss of heterozygosity (LOH) in the multiple synchronous lesions, while the remaining cases had different LOU patterns. In an extensively studied "golden case", the multiple carcinoma and cervical intraepithelial neoplasia (CIN) lesions could be divided into several different clonal groups by the X-chromosome inactivation patterns, HPV 16 mutations and LOH patterns. The biggest clonal family included one CIN II, one CIN III and four carcinoma samples, while four other monoclonal families of carcinoma did not include CIN lesions. These results suggested that cervical carcinoma can be either monoclonal or polygonal and contains clones developing either directly or via multiple steps. In the study of HPV types and HPV16 variations, the results confirmed that specific HPV types are the cause of cervical carcinoma but failed to support the previous opinion that HPV16 E6 variants are more malignant than the prototype. We established a novel classification called oncogene lineage of HPV16, and found that additional variations of HPV 16 oncogenes might be a weak further risk factor for cervical carcinoma. In the study of LOH, we found that interstitial deletion of two common regions of chromosome 3p, i.e., 3p2l.1-3p2l.3, and 3p22, was an early event in the development of cervical carcinoma. The results showed that the hMLH1 gene, located in 3p22 and showing LOH in 43% of the studied cases, was not involved in the development of cervical carcinoma because neither the expression level of protein nor the gene sequence was altered in these cases. In summary, a suggested model of molecular pathogenesis of cervical carcinoma is as follows. Specific types of HPV infect one or more committed stem cells in the basal layer of the epithelium. Fully efficient LOH events turn one (monoclonal origin) or more (polyclonal origin) HPV-infected stem cells into carcinoma cells without CIN steps. Less efficient LOH events would lead to CIN steps where some other unknown factors require to be added to facilitate the formation of carcinoma. In the absence of LOH events no carcinoma develops from the HPV-infected stem cells.