Le cancer du col utérin est précédé par des lésions prénéoplasiques. Celles-ci sont associées dans plus de 95% des cas à une infection par un papillomavirus (HPV). Un phénomène fréquent durant la cancérogenèse cervicale est l'intégration du génome dun HPV oncogène dans lADN cellulaire. Celle-ci entraîne une expression sélective de gènes codant pour des oncoprotéines virales (appelées E6 et E7) capables d'inactiver les produits de certains gènes suppresseurs de tumeurs (p53, p21, pRb) ou dinteragir avec dautres protéines cellulaires impliquées dans le contrôle du cycle cellulaire. Des travaux antérieurs du laboratoire daccueil suggèrent que le développement du cancer du col utérin est associé à une faible capacité de présentation dantigènes au système immunitaire, comme le démontre la rareté et le déficit fonctionnel des cellules de Langerhans (LC, cellules dendritiques ayant une fonction professionnelle de présentation antigénique au niveau de la peau et des muqueuses) dans les lésions (pré)cancéreuses cervicales. Ces altérations pourraient empêcher une réponse immunitaire efficace et faciliter la persistance du virus ainsi que la progression tumorale. Il est actuellement bien admis que les kératinocytes (cellules cibles de linfection par HPV) sont susceptibles dinfluencer les réactions immunitaires au niveau de la peau et des muqueuses épidermoïdes par lintermédiaire de facteurs solubles, les chémokines (CCL20, contrôlant linfiltration des LC immatures au sein de lépithélium) ou de contacts membranaires (E-cadhérine). Les kératinocytes infectés par HPV pourraient se différencier des cellules normales pour la production de ces facteurs, ce qui pourrait contribuer aux altérations des cellules de Langerhans/cellules dendritiques (LC/DC) observées dans les lésions (pré)cancéreuses cervicales. Le fait que la molécule dadhésion E-cadhérine intervienne dans lattachement des LC aux kératinocytes suggère limportance de cette molécule dadhésion dans la rétention des CL au sein de lépithélium cervical. Les objectifs de ce travail ont été détudier linfluence des oncogènes viraux sur lexpression de facteurs immunitaires et dexaminer les conséquences de linhibition de E6 et de E7 sur lexpression de la E-cadhérine et de CCL20, qui jouent un rôle important dans limmunosurveillance au niveau des épithélia via leur action sur les cellules de Langerhans. En accord avec notre hypothèse, nous avons montré une diminution de lexpression de la E-cadhérine dans les lésions (pré)néoplasiques du col par rapport à lépithélium exocervical normal (Hubert et coll. 2005). Par des expériences dARN interférence (siRNA), nous avons également démontré limplication de loncoprotéine virale E7 dans linhibition de lexpression de la E-cadhérine membranaire (Caberg et coll. 2008) et limplication des oncoprotéines virales E6 et E7 dans la diminution de la sécrétion de la chémokine CCL20 dans des kératinocytes transformés par HPV16 (Caberg et coll. 2008).

Human Papillomavirus (HPV) is a key factor in the development of cervical cancer. Out of the more than 100 known HPV types 13 are considered oncogenic. In addition to presence of the virus several other factors have been proposed to influence risk of cervical cancer. This thesis focuses on viral load and HLA class II alleles as risk factors for cervical cancer. To enable quantification of the most common oncogenic HPV types, a real-time PCR-based assay was developed and evaluated in terms of technical sensitivity and specificity. This assay was then employed on archival smears from 457 cases and 552 controls to assess associations between viral load and cervical carcinoma in situ (CIS). Whereas the data indicate a pronounced dose dependent effect of HPV 16 load on the risk of CIS, other HPV types only seem to increase CIS risk at higher viral loads. These effects were observed even when cytology indicated that cells were normal. We then investigated viral load as a risk factor for invasive cervical carcinoma (ICC) in a retrospective study comprising 139 cases and 550 controls. Viral load contributed similarly to the risk of ICC as to the risk of CIS. Finally, associations between HLA class II alleles, viral load and CIS were investigated. Carriers of the DRB1*1301 allele were less prone to infections and high viral loads of HPV 31 and -18/45. Moreover, DRB1*1301 had a protective effect against CIS among women infected by HPV 31 or -18/45. In contrast, carriers of DRB1*1501 and DQB1*0602 were more susceptible to infections and high viral loads of HPV 16. These results indicate that HPV load may have HPV-type specific effects on cervical cancer risk. Furthermore, HLA class II alleles may confer either susceptibility or protection against cervical cancer by acting on the HPV infections preceding tumor development.

Cervical cancer is a multifactorial disease. Infection by oncogenic types of the human papillomavirus (HPV) is the major environmental risk factor and host genetic susceptibility also influences disease development. The aim of this thesis is to identify and analyse risk genes involved in the genetic predisposition to cervical carcinoma. A unique and extensive population-based affected sib-pair (ASP) material and a large case-control sample were used in the investigations. In paper I the human leukocyte antigen (HLA) class II DQB1 and DRB1 loci are confirmed, for the first time in a family-based material, as genetic susceptibility factors for cervical cancer. It is also proposed that the HLA class II DPB1 locus independently contributes to risk of developing disease. In addition, no evidence is found for an involvement of the class I HLA-B and HLA-A loci in the genetic predisposition. Paper II conclude that the Fas receptor –670 single nucleotide polymorphism (SNP) do not have a major impact on the susceptibility to cervical carcinoma in situ in the Swedish population. In paper III we show that interactions between the HPV16 E6 gene subtype and host HLA class II genotype potentially occur during infection and disease progression. Paper IV suggests that three chromosomal regions, 9q32, 12q24 and 16q24, contain risk factors of low to moderate effects on cervical cancer development. In paper V linkage signals are further identified between a 9q32 gene encoding the thymic stromal co-transporter (TSCOT) and the disease in ASPs with mean age over 30.5 years at diagnosis within the sib-pair. These findings are important contributions towards understanding more about the aetiology of this complex cancer. The identification of new susceptibility regions opens up for further characterisation, replication and candidate gene analysis.

Women afflicted with cervical cancer who have the highest morbidity and mortality rates have been the least likely to be screened. The overall aim of this research project was to investigate non-attendance in a cervical cancer screening (CCS) program among women with no registered cervical smear during the previous five years. Both quantitative (I,III) and qualitative methods (II) as well as costeffectiveness analysis (IV) were used in this research project. In Kalmar County women (aged 23-65 years) are invited to CCS every third year. All cervical smears taken both in opportunistic and organised CCS are coordinated in a register called Sympathy. The coverage is 88.4 %. From Sympathy, a random sample of 400 women served as a study group and another 400 women as a control group (III,IV). From the study group, 133 women participated in study I and 14 women in study II. Data was collected by telephone interviews based on a questionnaire (I), qualitative face-to-face interviews (II), questionnaire, promotive efforts and outcome (III), costs and effectiveness (IV). Quantitative data was analysed by descriptive and analytic statistics (I,III), qualitative data was analysed by content analysis. In study IV, cost-effectiveness analysis was used. The women believed that CCS was a good idea for all other women, but tended to refer to various circumstances resulting in their own non-attendance. One of the most common reasons for non-attendance was the feeling of being healthy. The women prioritized family and work commitments, and the invitation to attend CCS was sometimes experienced as a stressful disturbance. The feeling of discomfort was related to the gynaecologic examination, or to health care visits in general (I,II). Of 133 women, 120 could consider having a cervical smear taken and their two most common requirements for doing so were to be assured they would be treated in a friendly way (19%) and to find a suitable time (18%) for having the cervical smear. Fifty women wanted to be helped to have a cervical smear taken. Promotive efforts ranged from making a simple telephone call to arranging an appointment time to a combination of promotive efforts including repeated encounters in order to create a trusting relationship with respect to taking the smear. In the study group, 29.5% (n=118) had a registered cervical smear at follow-up compared to 18.5% (n=74) in the control group, (p<0.001) (III). In the study group, the cost per cervical smear taken was 66.87 €, and in the control group it was 16.62 €. The incremental cost per additional cervical smear taken was 151.36 € (IV). In conclusion, women’s reasons for not attending CCS are complex and are influenced by both present and earlier circumstances. In settings with high coverage, further contact in order to promote women’s attendance at CCS seems to be associated with high costs in relation to the number of additional cervical smears taken. / On the day of the defence data the status of article I was: In press; article II: Submitted; article II: Accepted and artile IV: In press.

Background: In Canada, the prevalence of cervical cancer in Aboriginal women continues to increase with a significantly higher mortality rate than women of non-Aboriginal ancestry. Despite that invasive cervical cancer is highly preventable with regular cervical cancer screening, participation in screening remains lower among Aboriginal women. Since limited information exists on the way cervical cancer screening is perceived and experienced, the purpose of this study was to gain an understanding of Saskatchewan Aboriginal womens perceptions related to and experiences with cervical cancer screening.<p> Methodology: This qualitative exploratory study used an interpretive descriptive approach. Perceptions related to and experiences with cervical cancer screening were elicited through individual interviews with eleven Dakota First Nation women. Women were recruited through purposive sampling techniques. Initially direct quotes from individual transcripts were coded, and then organized with other participant quotes that reflected thematic similarities.<p> Findings: Shared insights reflected a main theme that described perceptions of, experiences with, and factors influencing cervical cancer screening participation among Saskatchewan Aboriginal women. This theme, transitioning from experiencing the negatives of cervical cancer screening participation to living healthier, consisted of the womens mind-set (attitudes and cultural beliefs), knowledge, encounters with the health care system, and sharing information across the generations, which included patterns of communication and a community oriented approach.<p> Discussion: Findings of this study suggest that improving knowledge about cervical cancer screening and cervical cancer may increase screening utilization. Emphasis on health promotion and prevention should be considered when designing education programs. Interventions designed to improve screening rates are more effective when community members are involved in each phase, ensuring cultural relevance. Improving knowledge about, experiences with, and stories shared regarding cervical cancer screening among Aboriginal women may increase screening rates.

Despite being the most preventable cancer, cervical cancer remains the third leading cause of cancer death worldwide. Over 85% of cervical cancer incidence and mortality occurs in low-resource countries where screening programs for early detection are either inadequate or unavailable. In the developed world, where screening programs are well organized, incidence and mortality rates are greatly reduced. Recent advances in optical imaging have the potential to enable cervical cancer screening at the point-of-care, even in the hands of less experienced providers. High performance optical imaging systems can be constructed at relatively low cost, and image analysis can be automated; thus, these technologies may provide a way to bridge the gap to cervical cancer screening for developing countries. This work focuses on the design, construction, and clinical testing of a novel multimodal optical imaging (combination of wide-field imaging and high-resolution) for early detection of cervical neoplasia. The Multimodal Digital Imager (MDI) acquires in vivo images of cervical tissue in fluorescence, narrow band reflectance, and orthogonal polarized reflectance modes using multiple illumination wavelengths. The High Resolution Microendoscope (HRME) was used to interrogate clinically suspicious areas with subcellular spatial resolution, revealing changes in nuclear to cytoplasmic area ratio. In vivo image data from the wide-field system was combined with image data from a high- resolution microendoscope (HRME) in order to test the effectiveness of the multimodal optical imaging in discriminating between cervical neoplasia and non-neoplastic. Multimodal optical imaging coupled with computer aided diagnostic achieved a sensitivity of 82% and specificity of 85% for discriminating cervical neoplastic from non-neoplastic This work has demonstrated that multimodal optical imaging; combination of wide-field and high-resolution optical imaging of the cervix can assist in the detection of cervical neoplasia and can be implemented effectively in a low-resource setting.

Background: In Canada, the prevalence of cervical cancer in Aboriginal women continues to increase with a significantly higher mortality rate than women of non-Aboriginal ancestry. Despite that invasive cervical cancer is highly preventable with regular cervical cancer screening, participation in screening remains lower among Aboriginal women. Since limited information exists on the way cervical cancer screening is perceived and experienced, the purpose of this study was to gain an understanding of Saskatchewan Aboriginal womens perceptions related to and experiences with cervical cancer screening.<p> Methodology: This qualitative exploratory study used an interpretive descriptive approach. Perceptions related to and experiences with cervical cancer screening were elicited through individual interviews with eleven Dakota First Nation women. Women were recruited through purposive sampling techniques. Initially direct quotes from individual transcripts were coded, and then organized with other participant quotes that reflected thematic similarities.<p> Findings: Shared insights reflected a main theme that described perceptions of, experiences with, and factors influencing cervical cancer screening participation among Saskatchewan Aboriginal women. This theme, transitioning from experiencing the negatives of cervical cancer screening participation to living healthier, consisted of the womens mind-set (attitudes and cultural beliefs), knowledge, encounters with the health care system, and sharing information across the generations, which included patterns of communication and a community oriented approach.<p> Discussion: Findings of this study suggest that improving knowledge about cervical cancer screening and cervical cancer may increase screening utilization. Emphasis on health promotion and prevention should be considered when designing education programs. Interventions designed to improve screening rates are more effective when community members are involved in each phase, ensuring cultural relevance. Improving knowledge about, experiences with, and stories shared regarding cervical cancer screening among Aboriginal women may increase screening rates.

Syfte: Syftet var att undersöka unga kvinnors inställning till hur de kan förebygga livmoderhalscancer. Vidare var syftet att undersöka vad de unga kvinnorna har för åsikter om information kring livmoderhalscancer.  Metod: Explorativ kvalitativ studie med semistrukturerade intervjuer användes. Kvinnor i åldern 16-18 år rekryterades på Ungdomshälsan i Uppsala med ett medvetet urval. Totalt genomfördes 20 intervjuer. Innehållsanalys med manifest ansats användes för att analysera data.  Resultat: Kvinnornas inställning till preventionsarbetet baserades på deras kunskap. Majoriteten av kvinnorna hade hört talas om ”ett vaccin” och de flesta hade en positiv inställning till det. De hade även en positiv inställning till kondom men det var ett flertal som inflikade att de inte trodde att den användes i praktiken. Den främsta anledningen till att unga kvinnor har kunskaper om livmoderhalscancer är på grund av informationen kring HPV vaccinet. Kvinnorna har främst erhållit informationen om vaccinet från media, mamma och kompisar. De önskade att skolan skulle ta ett större ansvar att ge information.  Slutsats: De unga kvinnorna som ingår i denna studie var positiva till att förebygga livmoderhalscancer. De anser att de inte har fått tillräckligt med information om livmoderhalscancer och att den kan förbättras. / Aim: The purpose of this study was to investigate young women´s attitudes to cervical cancer prevention. The aim was also to examine the young women´s opinions of information about cervical cancer.  Method: Explorative qualitative study using semi-structured interviews were used. Women aged 16-18 years were recruited at Youth Clinic in Uppsala and 20 interviews were performed. Conscious selection was used. Manifest content analysis was used to analyze data.  Results: Women's attitudes to prevention were based on their knowledge. The majority of women had heard of "a vaccine" and most had a positive attitude towards it. The majority of participants had a positive attitude towards condom but a number of informants mentioned that they did not believe that it was used in practice. The main reason that young women have knowledge of cervical cancer is due to the HPV vaccine. Women are primarily received information about the vaccine from the media, mother and friends. They wanted the school to take more responsibility to provide information.  Conclusion: The participants in this study were positive to prevention methods to cervical cancer. They think that they have not received enough information about cervical cancer and that the information can be improved.  Keywords:

Human telomerase is a ribonucleoprotein complex that adds hexameric TTAGGG repeats to the ends of chromosomes in order to prevent their shortening. Telomerase activity has been evaluated for its diagnostic and prognostic value in cancer since it is observed in most malignancies but not in most normal somatic tissues. In this study telomerase activity was examined in tumor specimens obtained from cervix, endometrium and their non-cancerous regions by an improved telomeric repeat amplification protocol (TRAP) &ndash / silver staining assay. Appearance of characteristic TRAP leader with 6 base pair increments indicate a positive result and was observed in all cancerous and some of the non-cancerous tissues. Telomerase activities of carcinoma tissues and normal counterparts were compared by densitometric analysis after PCR. Significantly higher telomerase activity was observed in cervical carcinoma samples compared to normal adjacent tissue. No significant difference was observed between endometrium carcinomas and normal endometrial tissue in terms of telomerase activity. High telomerase activity in normal endometrium restricts the use of assay for detection of carcinogenesis. However, in cervical tissues an accurate quantification of telomerase activity by TRAP &ndash / silver stain assay may be valuable as a confirmatory assay.

Aim The burden of cervical cancer in Sri Lanka is high and research is limited. The objective was to describe the knowledge of Human Papilloma Virus (HPV), cervical cancer and its cytological screening, as well as worry of HPV and attitudes towards and practices of screening among undergraduate students at Rajarata University of Sri Lanka, Mihintale. Methods A cross-sectional study was conducted in January 2015 at Rajarata University, using a self-administrated questionnaire containing socio-demographics, knowledge, attitudes and practices (KAP). Male and female undergraduates, 18-30 years, were eligible. Knowledge was assessed by a numerical sum score ranging from 0 to 13, with 13 as maximum. Analyses were performed using ANOVA or Kruskal-Wallis tests. Results 326 students answered the questionnaire that revealed limited knowledge on cervical cancer, HPV and screening, with a mean score of 5.34 (SD 3.33). Knowledge was higher among older, medical students in the fifth year, however there was a high correlation between these variables. Knowledge was lower among management students. Most students were uncertain about the questions in the attitude section. A majority of students would be worried if they got infected with HPV. Screening practices were low (0.45 %). Approximately half of the women would consider cytological screening in the future. Conclusion The limited knowledge, low screening practices and high worry imply a need for information and awareness programs. Further research is needed in order to fully understand the delicacy of this public health threat for Sri Lankan women.