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- Jalouli, Jamshid, 1959-
(författare)
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Human Papilloma Virus, Epstein-Barr Virus, and Herpes Simplex Virus Type-1 in Oral Squamous Cell Carcinomas from Three Populations
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Most oral squamous cell carcinoma (OSCC) is believed to develop via a multistep process of cumulative gene damage in epithelial cells. Increasing incidence of OSCC and evidence that traditional risk factors may not be responsible directed us to investigate the prevalence of virus in pre- and malignant samples.The integration of the DNA from human papillomavirus (HPV), Epstein-Barr virus (EBV), and Herpes simplex (HSV) into the human genome is associated with the expression of oncogenes and the down-regulation of tumor-suppressor genes in OSCC carcinogenesis. This thesis compared samples from India and Sudan, two countries on two continents having a documented high incidence of oral cancer, with specimens from Sweden, with its known low incidence of oral cancer. Each region has, in addition to smoking, a unique non-smoked tobacco habits with documented carcinogenic effects. These countries also typify areas of low and high socioeconomic living conditions with their expected impact on disease development. The study populations were selected from tobacco users and nonusers with OSCC, oral sub-mucous fibrosis (India), oral lichen planus (Sweden), oral leukoplakia with and without dysplasia and snuff-induced lesions (Sweden and Sudan). An expedient method was developed for extracting DNA from old formalin-fixed and paraffin-embedded biopsies. The prevalence of HPV, EBV, and HSV was investigated using PCR/DNA sequencing and southern blot hybridization analysis. We found HPV and EBV to be most prevalent in samples of tissue characterized as normal, with decreasing prevalence in dysplastic and malignant lesions. This intriguing finding that prevalence decreases as neoplastic development proceeds warrants further investigation. Our data do not at first sight support the conclusion that viruses and tobacco use jointly interact with cell mechanisms in the development of oral cancer.
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| 2. |
- Kaliff, Malin, 1985-
(författare)
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Human papillomavirus and cellular biomarkers in cervical cancer
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cervical cancer (CC) is caused by a persistent infection of certain types of the human papillomavirus (HPV). Even though great progress has been made in strategies for prevention, and treatment of CC, there is still a need for improved methods in screening and management of women diagnosed with CC. The aim of this thesis was to gain further knowledge of CC by studying HPV-related or cellular biomarkers in precursors and established cancer.Mostly molecular methods were used for analysis of both tumour and screening samples. Among the studied biomarkers were HPV genotype, HPV multiplicity, viral load and methylation.Initially, HPV was detected in only 86% of the tumours; after careful reinvestigation of the negative samples, the final prevalence was 93%. The results show that analysis of long-term archived samples may require thorough and repeated analysis to obtain accurate results. In the HPV-positive tumour samples, 13% tested positive for multiple genotypes. This finding was associated with poor prognosis for the woman and could be a useful biomarker for prognostic assessment in CC. Viral load was analysed as a potential contributing factor for prognosis differences, however, no such association was detected.In the screening cohort, 40% of women with high-grade abnormalities were positive for HPV16 and 18, genotypes included in the vaccine used since 2012 in Sweden, while 88% were positive for the genotypes in the updated vaccine used since 2019. This indicates a large future reduction of high-grade abnormalities in the vaccinated cohorts, and baseline data like these are valuable for surveillance of genotype distribution in the coming decades. A methylation test targeting two human genes, proposed for use in screening, was tested on the screening samples. We detected no association between hypermethylation and HPV, but it was associated with increasing age, something that needs to be considered if using this method in screening.
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| 3. |
- Lindquist, David
(författare)
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Studies on the occurrence and effects of human papillomavirus in tumors of the head and neck
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The presence of human papillomavirus (HPV) in squamous cell carcinoma of the head and neck (HNSCC) was first reported in 1985. Since then, this association has been studied intensively and today there is substantial evidence for HPV as a causative agent and positive prognostic factor for clinical outcome in tonsillar cancer, but the association to other HNSCC is still unclear. The aim of this thesis was first to examine the presence of HPV in tongue cancer and to study its possible influence on disease outcome. Thereafter, the association between HPV and cdk inhibitor p16INK4a expression and a possible correlation to response to radiotherapy (RT) and survival was studied. A third aim of this thesis was to investigate if HPV is a potential risk factor for the increase in incidence of tonsillar cancer that has been observed in Sweden. Furthermore, presence of HPV, viral load and expression of the viral oncogenes E6 and E7 in tonsillar cancer was investigated and correlated to clinical outcome. In tongue cancer, HPV DNA detected by PCR was more commonly found in base of tongue cancer (40%) as compared to mobile tongue cancer (2.4%), and was a positive prognostic factor for survival in patients with base of tongue cancer. This finding indicates that HPV might not only be involved in tonsillar cancer, but also in base of tongue cancer, which has a similar histology and is also a part of oropharynx. In tonsillar cancer there was a strong correlation between a high expression of p16INK4a detected by immunohistochemistry (IHC) and presence of HPV detected by PCR. However, only high expression of p16INK4a, and not the presence of HPV, was shown to be a predictive factor for complete response to RT in tonsillar cancer. Nevertheless, both p16INK4a and HPV were positive predictive factors for clinical outcome. The incidence of tonsillar cancer and presence of HPV was studied in the Stockholm area during 1970-2002. HPV was detected by PCR in 49% of the patient samples and 87% of these were positive for HPV-16. The frequency of HPV positive tonsillar cancer increased 2.9-fold from 1970 to 2002 and during the same time period a parallel 2.8-fold increase in the incidence of tonsillar cancer was observed. These results strongly support HPV as a risk factor for the increase in incidence of tonsillar cancer. In the tonsillar cancer patients above, the finding of HPV as a positive prognostic factor in tonsillar cancer for clinical outcome was confirmed. In addition, HPV viral load and expression of the viral oncogenes E6 and E7 was analyzed with real time quantitative PCR and reverse transcriptase PCR in the HPV-16 positive tonsillar cancer samples. In most HPV-16 positive tumors, expression of E6 and E7 was ascertained. However, in contrast to earlier studies a high viral load was not correlated to survival. The findings of an increase in incidence of tonsillar cancer and a parallel increase in frequency of HPV positive tumors, a better disease specific survival, and the expression of viral oncogenes strongly support previous findings that HPV positive tonsillar cancer should be considered a different disease entity. If the now available prophylactic vaccines are included in the childhood vaccination program for girls, the possible effects on HPV positive tonsillar cancer should be discussed, since most patients with HPV positive tonsillar cancer are men.
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