Squamous cell carcinoma (SCC) and adenocarcinoma (ADC) are the most common histological types of cervical cancer (CC). The worse prognosis of ADC cases highlights the need for better molecular characterization regarding differences between these CC types. RNA-Seq analysis of seven SCC and three ADC human papillomavirus 16-positive samples and the comparison with public data from non-tumoral human papillomavirus-negative cervical tissue samples revealed pathways exclusive to each histological type, such as the epithelial maintenance in SCC and the maturity-onset diabetes of the young (MODY) pathway in ADC. The transcriptional regulatory network analysis of cervical SCC samples unveiled a set of six transcription factor (TF) genes with the potential to positively regulate long non-coding RNA genes DSG1-AS1, CALML3-AS1, IGFL2-AS1, and TINCR. Additional analysis revealed a set of MODY TFs regulated in the sequence predicted to be repressed bymiR-96-5p ormiR-28-3p in ADC. These microRNAs were previously described to target LINC02381, which was predicted to be positively regulated by two MODY TFs upregulated in cervical ADC. Therefore, we hypothesize LINC02381might act by decreasing the levels ofmiR-96-5p andmiR-28-3p, promoting the MODY activation in cervical ADC. The novel TF networks here described should be explored for the development of more efficient diagnostic tools.

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Bakgrund: År 2020 rapporteras det globalt 604 000 nya fall av livmoderhalscancer. I 90% av fallen skedde dessa i låg- eller medelinkomstländer. Den vanligaste orsaken till livmoderhalscancer är infektion med HPV-virus som är en sexuellt överförbar infektion. Behandlingen vid livmoderhalscancer är kirurgi, cytostatika, strålbehandling och kombinerad behandling med cytostatika och strålning. En god hälsa är en grundläggande mänsklig rättighet och en fundamental del av människans generella hälsa är sexuell hälsa. Syftet: Syftet var att belysa kvinnors upplevelse av sexuell hälsa vid diagnostiserad livmoderhalscancer. Metod: Studien är en kvalitativ litteraturöversikt med induktivt förhållningssätt där 14 artiklar har analyserats enligt analys av Friberg i fem steg. Resultat: Huvudkategorierna som framträdde var sexuellt lidande med underkategorierna sexuell hälsa relaterat till fysiska besvär och sexuell hälsa relaterat till psykiska besvär. Andra huvudkategorin är sexuellt välbefinnande med underkategorierna sexuellt intresse och stöd av vården. Slutsats: Livmoderhalscancern påverkade välbefinnandet och sexuella hälsan för kvinnor på ett negativt sätt. Resultatet visade att kvinnors självkänsla och kroppsbild förändrades med livmoderhalscancern och behandlingen och att fysiska symtom gjorde att kvinnorna upplevde en förändrad sexualitet. I de fall där kvinnorna upplevde en förbättrad sexuell hälsa och kunde återgå till ett fungerande sexliv hade partnern ett stöttande förhållningssätt och sjukvården hade försett dem med information och kunskap. / Background: In 2020, 604 000 new cases of cervical cancer were reported globally. 90% of these cases took place in low- or middle-income countries. The most common cause of cervical cancer is infection with the HPV virus, which is a sexually transmitted infection. The treatment for cervical cancer is surgery, cytostatics, radiotherapy as well as combined treatment with cytostatics and radiation. Satisfactory health is a basic human right and a fundamental part of a person's general health is their sexual health. Aim: The aim was to describe women’s experience of sexual health when diagnosed with cervical cancer. Method: The study is a qualitative literature review with an inductive approach where 14 articles have been analyzed according to analysis by Friberg in five steps. Result: The main categories that emerged were sexual suffering with the subcategories sexual health related to physical problems and sexual health related to psychological problems and the main category sexual well-being with the subcategories sexual interest and support from caregivers. Conclusion: Cervical cancer affected quality of life and sexual health of women in a negative way. The results showed that women's self-esteem and body image changed with cervical cancer and treatment and that physical symptoms caused the women to experience a changed sexuality. In cases where women experienced improved sexual health and were able to return to a functioning sex life, their partners had a supportive approach and health care had provided them with information and knowledge.

Text in English / Cervical cancer remains the leading cause of cancer mortality among women worldwide, a burden in the developing countries and commonly detected through symptoms at later invasive stages. The study aimed at establishing knowledge and awareness of the importance of cervical cancer screening in the Makhuduthamaga Sub-district by exploring the perceptions of women and professional nurses and through the review of the National Cervical Cancer Screening Policy (2013). Recommendations to address the gap in knowledge and to inform the National Cervical Cancer Screening Policy were developed based on the study findings. A mixed-method approach was used in this study through a sequential explanatory design, which is quantitatively driven was used. Quantitative data were obtained by using a researcher developed checklist. The checklist was developed from variables stated in the National Cervical Cancer Screening Policy and was used to review its implementation. Qualitative data was obtained through in-depth interviews with individual women and focus group discussions with professional nurses. The study was conducted in ten randomly selected clinics of Makhuduthamaga Sub-district. Purposive sampling was done to obtain qualitative data. An average score of 9.7 was obtained for all ten clinics that participated in the study with regard to the evaluation of the implementation of the National Cervical Cancer Screening Policy. Only 6 (60%) clinics implemented the policy whereas 4 (40%) clinics did not implement the policy. Women and professional nurses perceived cervical cancer screening as important. Lack of knowledge among women regarding cervical cancer screening contributed to the majority of women not screening for cervical cancer. Lack of resources, the 10 year interval of normal cervical cancer screening, the use of disposable vaginal speculums and brushes, lack of standardized cervical cancer screening training, centralization of cytology laboratories came out as factors that negatively influence the uptake of cervical cancer screening. Cervical cancer screening awareness campaigns, availability of resources and standardized in-service trainings on cervical cancer screening were recommended to enhance the cervical cancer screening uptake. Key concepts: / Health Studies / D. Litt. et Phil. (Health Studies)

This qualitative study explored and described the experience of African women diagnosed with both HIV/AIDS and cervical cancer in order to gain an understanding of the experience of both illnesses as lived by these women. Phenomenological research methods were employed using in-depth semi-structured interviews. Communication as a strategy facilitating diagnosis, disclosure, acceptance and support for women with HIV/AIDS and cervical cancer emerged as the main theme, followed by the experience of physical symptoms and emotional experiences. The study shows the importance of communication in the management and support of these women attending public health institutions and in the community. For communication to occur the relationship between healthcare professionals and women diagnosed with HIV/AIDS and cervical cancer is very important. Treatment approaches in radiation therapy need to be developed for women diagnosed with HIV/AIDS and cervical. More research is needed in this area (HIV/AIDS and cervical cancer). / Health Studies / M.A. (Public Health)

Le virus du papillome humain (HPV) est l’infection sexuellement transmise la plus fréquente au monde. Plusieurs études ont établi son implication dans l’étiologie de pratiquement tous les cancers du col de l’utérus, une maladie qui constitue un problème de santé majeur dans les pays pauvres. Le HPV est également responsable de 90% des cancers de l’anus, 40-50% des cancers du pénis, de la vulve et du vagin, et 30% des cancers de la tête et du cou. L’objectif général de cette thèse est de combler les lacunes relatives aux connaissances sur la distribution génotypique du HPV dans les lésions néoplasiques cervicales utérines et de la tête et du cou, plus particulièrement en Afrique. Les objectifs spécifiques sont les suivants: 1) analyser la distribution génotypique du HPV dans les cancers du col de l’utérus et faire une analyse comparative de cette distribution dans cinq pays africains en fonction de la prévalence du VIH; 2) évaluer la présence du HPV dans les cancers de la tête et du cou au Sénégal; 3) faire une revue de la littérature et une méta-analyse sur la distribution du HPV dans les cancers de la tête et du cou dans toutes les régions du monde. Pour le premier et le second objectifs, qui découlent d’un large projet international coordonné par l’Institut Catalan d’Oncologie pour l’Organisation Mondiale de la Santé (OMS), une étude transversale multicentrique a été menée au Mali et au Sénégal pour collecter des blocs de paraffine de patientes diagnostiquées entre 2001 et 2010 du cancer invasif du col et des cancers de la tête et du cou. Pour le troisième objectif, une revue exhaustive de la littérature a permis d’identifier tous les articles qui ont été publiés sur les cancers de la tête et du cou dans tous les pays du monde et d’effectuer une méta-analyse sur la prévalence de l’ADN du HPV selon le site du cancer et la région géographique. Notre analyse montre que les principaux types de HPV ciblés dans les vaccins prophylactiques (HPV16/18) représentent la majorité des types de HPV détectés dans le cancer invasif du col de l’utérus en Afrique subsaharienne. Par contre, le HPV45 vient au second rang dans certains pays d’Afrique, dont le Mali et le Sénégal. Nos données suggèrent également que le VIH aurait un rôle dans la contribution relative du HPV18 et HPV45 dans le développement du cancer du col de l’utérus. Au Sénégal, notre étude montre que la prévalence du HPV dans les cancers de la tête et du cou est très faible et ne semble pas jouer un rôle important dans l’oncogenèse. Finalement, la méta-analyse a mesuré la prévalence des HPV dans les cancers de la cavité orale, de l’oropharynx, du larynx et de l’hypopharynx, et confirme l’importante contribution relative du HPV16 dans ces cancers. Globalement, cette thèse permet de mieux comprendre l’impact potentiel des vaccins prophylactiques sur l’incidence des cancers associés au HPV. / Human papillomavirus (HPV) infection is the most common sexually transmitted infection worldwide. Several studies have shown its involvement in the etiology of virtually all cancers of the cervix, which is a major health problem in poor countries. HPV is also responsible for 90% of anal cancers, 40-50% of penile, vulvar and vaginal cancers, and 30% of head and neck cancers. The overall objective of this thesis is to fill the gaps in knowledge on the genotype distribution of HPV in anogenital and head and neck neoplasia, especially in sub-Saharan Africa. The specific objectives are to: 1) analyze HPV genotype distribution in cervical cancer and compare this distribution in five African countries according to HIV prevalence; 2) evaluate the presence of HPV in cancers of the head and neck in Senegal; 3) review the literature on the distribution of HPV in cancers of the head and neck in all regions of the world and perform a meta-analysis. For the first and second objectives, which were derived from a larger international project coordinated by the Catalan Institute of Oncology for the World Health Organization (WHO), a cross-sectional multicentric study was conducted to collect paraffin-embedded blocks of invasive cervical cancer and head and neck cancer diagnosed between 2001 and 2010 in Mali and Senegal. For the third objective, a comprehensive search of the literature was conducted to identify all articles published to date on head and neck cancer. A meta-analysis was performed to estimate the prevalence of HPV DNA according to cancer site and geographical region. Our analysis shows that the main HPV types targeted in the prophylactic vaccines (HPV16/18) accounted for the majority of the HPV types found in invasive cervical cancer in sub-Saharan Africa. Our data also suggests that HIV may play a role in the contribution of HPV18 and HPV45 to the development of cervical cancer. However, HPV45 ranks second in many African countries, notably in Mali and Senegal. In Senegal, our study shows that HPV DNA prevalence in head and neck cancer is very low and is not importantly involved in the oncogenesis. Finally, the meta-analysis measured the prevalence of HPV in cancers of the oral cavity, oropharynx, larynx and hypopharynx, and confirmed the significant relative contribution of HPV16 in these cancers. Overall, this thesis contributes to a better understanding of the potential impact of HPV prophylactic vaccines on the incidence of HPV-associated cancers.

Arrière-plan: les cellules tumorales circulantes (CTC) sont détectables dans de nombreux cancers et peuvent être utiles cliniquement pour le pronostic de la maladie, pour mesurer la récidive et pour prédire la sensibilité aux medicaments chimiothérapeutiques. Au cours des dernières années, l’études des CTC dans de nombreux cancers tels que le cancer du sein, du poumon, du côlon et de la prostate a grandement évolué. Alternativement, il y peu d'études à ce sujet concernant le cancer du col de l’utérus (CCU). Objectifs: Notre objectif est d’optimiser le processus d'enrichissement des CTC dans le CCU et la détection moléculaire des biomarqueurs E6 et E7. Matériel et Méthodes: Dans l’optique de mimer la présence de CTC dans le sang, nous avons dilué des cellules cancéreuses CaSki VPH16-positif provenant d’un CCU dans du sang humain prélevé sur des volontaires sains. Les CaSki ont été collectées suite à une centrifugation par densité avec le Ficoll, la lyse des globules rouges (RBC) et la lyse des RBC combinée avec un enrichissement positif et négatif à l’aide de marqueurs de surface cellulaire. Les CTC ont été détectées par la mesure d’expression des oncogènes E6 et E7 du virus du papillome humain (VPH), de la cytokératine 19 (CK19) et de la cycline p16INK4 en utilisant la technique quantitative en temps réel de Reverse Transcriptase-Polymerase Chain Reaction (qRT-PCR). Pour valider notre méthode de détection des CTC in vivo, nous avons recruté dix patientes atteintes d’un CCU VPH16 positif et six contrôles sains. Résultats: Dans le modèle de dilutions de cellules CaSki, la lyse des RBC seule ou combinée avec l'enrichissement négatif ou positif suggèrent des limites de détection de 1 CTC par mL de sang pour tous les biomarqueurs moléculaires utilisés. La sensibilité de détection est accrue lors de l'utilisation de l’enrichissement positif et négatif en réduisant le bruit de fond causé par les monocytes sanguins. Contrairement aux oncogènes E6 et E7, les marqueurs CK19 et p16INK4A ont été détectés chez des individus sains, les niveaux d'expression de base appropriés doivent donc être déterminés avec précision par rapport aux patientes CCU. Le gradient de densité par Ficoll a une limite de détection de seulement environ 1000 cellules par mL de sang. Enfin, les CTC ont été détectées dans 2/10 patientes en utilisant le marqueur CK19. Cependant, ces patientes étaient négatives pour les oncogènes E6/E7. Le marqueur p16INK4A était exprimé au même niveau dans tous les échantillons (CCU et normaux). Conclusion: Notre étude suggère que les oncogènes E6 et E7 du VPH16 sont les marqueurs biologiques les plus sensibles et spécifiques en qRT-PCR pour détecter les CTC dans le modèle de dilution de cellules de CCU dans le sang. Chez les patientes atteintes d’un CCU de stade précoce, seulement CK19 a révélé la présence potentielle de CTC, ce qui suggère que ces cellules sont rares à ce stade de la maladie. Mots clés: cancer du col de l’utérus, cellules tumorales circulantes, RT-qPCR, E6 et E7, CK19, p16INK4A, enrichissement immunomagnétique, détection moléculaire. / Background: Circulating tumor cells (CTCs) have been detected in many cancers and are used in multiple clinical applications including disease prognosis, tumor recurrence prediction and prediction of tumor sensitivity to chemotherapeutic drugs. Studies in most major solid cancer(s) (breast, lung, colon and prostate) are progressing rapidly, but there has been very little progress concerning uterine cervical cancer (UCC).Objective: our aim is to optimize enrichment processes and the molecular biomarker-based detection of human circulating tumor cells (CTCs) in uterine cervical cancer (UCC). Material & Methods: To mimic CTCs in patients, we designed an experimental spiking model where the CaSki HPV16-positive UCC cell line was serially diluted and spiked into human blood collected from healthy volunteers. CaSki CTCs were enriched using either Ficoll density centrifugation, red blood cell (RBC) lysis or RBC lysis combined with cell surface markers negative or positive enrichment. CTCs were detected using real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR) to measure the gene expression of human papillomavirus (HPV) viral oncogenes (E6 and E7), cytokeratin 19 (CK19), or the cyclin dependent kinase inhibitor p16INK4A. Finally, ten HPV16- positive UCC patients and six healthy controls were recruited to validate CTCs detection in vivo. Result: In the spiking model, RBC lysis alone or combined with negative or positive enrichment suggests detection limits close to 1 CTC per mL of blood for all molecular biomarkers used. The sensitivity of detection increased when using positive and negative enrichment probably by reducing the peripheral blood mononuclear cell-derived RNA background. Unlike HPV oncogenes, CK19 and p16INK4A were detected in normal individuals, thus appropriate basal expression levels need to be accurately determined compared to cancer patients. Alternatively, Ficoll density gradient had a detection limit of only about 1000 cells per mL of blood. Finally CTCs were detected in 2/10 patients using CK19. None of the patients had E6/E7 transcripts and p16INK4A was expressed at similar level across all samples (cancer and healthy). Conclusion: qRT-PCR of HPV16 E6 and E7 is the most sensitive and specific biomarker used to detect CTCs in the spiking model. In early disease UCC patients, only CK19 revealed the presence of CTCs suggesting that these cells are rare at that stage of the disease. Keywords: uterine cervical cancer, circulating tumor cells, qRT-PCR, E6 and E7 oncoprotein, CK19, p16INK4A, immune-magnetic enrichment, molecular detection.

The study is informed by inadequate information on factors associated with the prevalence, incidence and mortality of cervical cancer cytological abnormalities in Swaziland. The aim of the study was to explore and describe factors associated with cervical cancer among women of reproductive age between 15 and 49 years in Swaziland. Quantitative descriptive design with a data extraction tool was used to retrospectively generate observational data from 1748 patients’ records in Mbabane Government Hospital from January 2014 through to December 2014. Bivariate logistic regression was used to establish relationship between cervical cancer and each explanatory variable. The overall prevalence of cervical cytology test results was 24.9%. The combination of marital status, HIV status, ART status, age at sexual debut have been identified as factors associated with cervical abnormalities. Most importantly, the results will also serve as evidence for the development of a national cervical cancer screening policy and also strengthening the cancer registry in Swaziland. / Health Studies / M.A. (Public Health)

Nos últimos anos, inúmeros estudos epidemiológicos evidenciaram a forte associação entre o carcinoma do colo uterino e a infecção por papilomavírus humano (HPV). Esta associação deriva do reconhecimento de que estes vírus codificam oncoproteínas, dentre as quais E6 e E7, que apresentam propriedades transformantes. O produto do gene E7 se liga ao produto do gene retinoblastoma que perde a sua função de regular negativamente o ciclo celular. O produto do gene E6 se liga ao produto do gene supressor de tumor p53 levando a sua degradação pela via de proteólise dependente de ubiquitina. O gene p53 é um supressor tumoral com função de regulação do ciclo celular que apresenta vários polimorfismos distintos em diversos grupos étnicos e tem sido amplamente estudado tanto em tecidos normais quanto em tecidos tumorais. O polimorfismo do códon 72 do gene i>p53 é o mais estudado e pode apresentar três alelos diferentes na população. Um alelo codifica arginina (Arg), um codifica prolina (Pro) e outro, raramente encontrado, codifica cisteína (Cys). Em 1993 foi iniciado um estudo epidemiológico da história natural da infecção por HPV e neoplasia da cérvice uterina em uma população feminina de baixa renda em São Paulo (Brasil), uma das áreas de maior risco em todo o mundo. O estudo focaliza a infecção persistente por tipos oncogênicos de HPV como evento precursor que leva à carcinogênese do colo do útero e visa entender os atributos da história natural da infecção viral e das doenças associadas ao colo uterino. Um dos objetivos deste estudo é avaliar se o polimorfismo do códon 72 do gene p53 pode, ou não, ser utilizado como marcador de predisposição ao câncer do colo do útero uma vez que um estudo inicial relatou que pacientes portando o genótipo p53Arg homozigoto seriam 7 vezes mais susceptíveis ao desenvolvimento de neoplasia da cérvice uterina que pacientes contendo o genótipo p53Pro e heterozigoto p53Pro/ Arg. Contudo, vários estudos posteriores contradizem e corroboram esses achados. O presente projeto teve como objetivos, portanto, verificar se o polimorfismo do códon 72 do gene p53 poderia estar associado a infecções persistentes por HPV e ao risco de neoplasia do colo do útero, além de comparar metodologias de detecção utilizadas por outros estudos, visando esclarecer se os motivos que levam à discordância dos resultados podem ser atribuídos a ocorrência de erros classificatórios metodológicos. Ao todo, sete metodologias de detecção foram comparadas. Apenas uma delas, PCR alelo-específica, apresentou resultado discordante das demais utilizadas. Coincidentemente, essa metodologia foi amplamente utilizada por muitos estudos que encontraram associações tanto positivas quanto negativas. Isso poderia nos dar indícios de que os erros classificatórios dependentes de metodologia poderiam influenciar os resultados de correlação entre o polimorfismo do códon 72 e o risco de neoplasia do colo do útero. As correlações observadas por este trabalho entre este polimorfismo do códon 72 e o risco de neoplasia do colo uterino não mostraram associação deste polimorfismo com o risco de infecções persistentes por HPV e as lesões precursoras do carcinoma do colo uterino. / In recent years, a number of epidemiological studies have pointed toward a strong association between cervical cancer and infection by Human Papillomavirus (HPV). This association derives from the discovery that these viruses code for oncoproteins, among them E6 and E7 that have transforming properties. The E7 gene product associates with the retinoblastoma gene product, causing the latter to lose its function as a negative regulator of the cell cycle. The E6 gene product interacts with the tumor suppressor p53 gene product, resulting in its degradation via ubiquitin dependent proteolysis. The p53 gene is a tumor suppressor that funcions in the regulation of the cell cycle. It presents a number of distinct polymorfisms in diverse ethnic groups, and has been widely studied, both in normal and tumor tissues. The polymorfism of codon 72 is the most studied, and may present three different alleles in the population. One allele codes for arginine (Arg), another codes for proline (Pro), and a third, rarely found, codes for cystein (Cys). In 1993 an epidemilogical study of the natural history of infection by HPV and its possible association with cervical neoplasia was initiated in a population of low income females in São Paulo, Brazil, one of the areas of greatest risk in the world. The study focuses on persistent infection by oncogenic types of HPV as a precursor to carcinogenesis of the cervix, and seeks to understand the attributes of the natural history of viral infection and of illnesses associated with the cervix. One of the objectives of the study is to evaluate if the polymorfisms of codon 72 of p53 can or not be used as a marker of predisposition to cervical cancer, given the finding in the initial study that patients who were homozygous for the p53Arg genotype were 7 times more susceptible to developing cervical neoplasias than those patients who were homozygous for p53Pro, or heterozygous p53 Pro/ Arg. Previous studies have been realized both supporting and disputing these findings. The current study had two main objectives: to verify if the polymorfism of p53 codon 72 could be associated with persistent infections of HPV and the risk of cervical neoplasia, as well as to compare methods of detection used by other studies, in an attempt to clarify if the discording results of past studies could be due to methodological classification errors. Seven detection methods were compared. Only one of these, allele specific PCR, presented discording results from the rest. Coincidentally, this method was widely used in a number of studies which found both positive and negative associations. This might indicate that the method-dependent classification errors could influence the results of correlation between codon 72 polymorphism and the risk of cervical neoplasia. The correlations observed by this study did not demonstrate an association between codon 72 polymorphism and the risk of persistent HPV infection and precursor lesions of cervical cancer.