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Thesis (Ph.D.) - University of Queensland, 2006. / Includes bibliography.

Objectives To analyze the prevalence and pattern of HPV infection in women of different age groups in Hong Kong, with respect to liquid-based cytologic diagnosis. Materials and Methods A total of 2,055 liquid-based gynecologic cytology cases using either SurePath or ThinPrep during the period from July 1, 2007 to July 31, 2012 were retrieved from the archival files of CH Pathology Limited for retrospective analysis. Cytologic diagnosis was first given. Polymerase chain reaction (PCR)-based human papillomavirus (HPV) genotyping was subsequently performed in cases either as requested simultaneously by gynecologists or if the cytologic diagnosis was “atypical squamous cells of undetermined significance (ASC-US)” or above. IBM SPSS statistics 20 was used for data analysis and assessment of possible statistical significance. Results The overall prevalence of HPV infection in the studied population was 67.7%, with 37.2% cases with “negative” cytologic findings being HPV positive. Cases with “lowgrade squamous intraepithelial lesion (LSIL)”, “atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H)” and “high-grade squamous intraepithelial lesion (HSIL)” were highly associated with HPV infection (97.8%, 91.5% and 98.4%, respectively). Amongst the “ASC-H” and “HSIL” cases, most of them were shown to harbor high-risk HPV DNA (87.2% and 93.4%, respectively). The overall prevalence of HPV infection was higher in women younger than 25 years and in women older than 54 years, with the peak at post-menopausal age group. The patterns for infection by single HPV genotype or high-risk HPV genotype(s) alone were similar to the overall pattern, with the first peak at women younger than 25 years, followed by a drop at aged 25 to 34 and rebound again when age afterward. As for infection by multiple HPV genotypes or low-risk HPV genotype(s) alone, the patterns were less consistent. Amongst all the HPV-positive cases, the commonest high-risk HPV genotypes were type 52 and type 16. HPV type 62 and type 81 represented the commonest low-risk HPV genotypes detected in the population studied. Infection by other HPV genotypes showed various patterns in different age groups. Conclusions The overall prevalence of HPV infection in Hong Kong females correlates with age of the patients and corresponding cytologic diagnosis. Women younger than 25 years and older than 54 years are more likely to harbor HPV. The patterns of HPV infection in local patients can be useful in future preventive measures such as vaccination. / published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Despite the advance in modern oncology, there was limited improvement over the survival outcome of head and neck cancers. Until the discovery of the etiological association between Human Papillomavirus (HPV) and oropharyngeal cancer, an accelerated evolution in the field of head and neck oncology began. This viral-related tumor has ignited tremendous effort in American and European countries to explore the optimal treatment approaches. In contrast, the paucity of comprehensive and robust studies commonly exists in many Chinese and Asian countries. Little is known about the current situation of HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) in Hong Kong. This retrospective local multi-institutional study attempted to explore the HPV-associated OPSCC in Hong Kong from various aspects, including demographics, risk factors, clinical and histological features, molecular profile, as well as clinical outcomes. Finally, attempts were made to determine any predictive factors to stratify high-risk patients in this distinct disease entity and explore the most appropriate detection algorithm of the biologically active HPV infection in our locality. With the support from the Hong Kong Cancer Registry and nine public hospitals, 141 (43.3%) of 326 newly diagnosed OPSCC in the whole population of Hong Kong between 2005 and 2009 were recruited. Inclusion criteria were histologically proven OPSCC with tumor specimens available for prospective laboratory tests. Those with non-SCC, non-oropharyngeal in origin and incomplete clinical records were excluded. Prospective HPV PCR and genotyping, and immunohistochemical staining with p16, p53, cyclin D1 and HER-2 were performed. Univariate and multivariate analyses were performed to assess the correlations between various parameters and HPV-associated OPSCC. Epidemiologically, based on the combined positivity in HPV PCR and p16, the prevalence of HPV-associated OPSCC was 22%. Thirty (96.8%) of thirty one were HPV-16, the remaining one was HPV-18. In the univariate analysis, this cancer directly correlated with female gender (p=0.014), younger age (p=0.012), non-smoker (p=0.02), non-drinker (p=0.06) and early primary tumor (p=0.001). Histologically, basaloid differentiation (p<0.001), non-keratinization (p=0.007) and high tumor infiltrating lymphocyte (TIL) level (p<0.001) showed significant correlations. A distinct molecular profile was identified, with p16 positivity noted in all cases (p<0.001), few of p53 (p<0.001) and cyclin D1 positivity (p<0.001) and absence of HER2 over-expression. Significantly superior prognosis was demonstrated in HPV-associated OPSCC. The 5-year overall and disease specific survivals were 67.0% and 88.6% compared with 27.8% (p<0.001) and 41.3% (p<0.001) in the non-viral counterpart respectively. Other good prognostic factors identified for OS and DSS included early primary disease (T1/T2) (p=0.02; p=0.001), absence of distant metastasis (both p<0.001), high TIL level (both p<0.001), p16-positivity (p=0.002; p=0.003), non-smoker (p=0.021; p=0.014). In the multivariate analysis, the HPV-associated tumor (HR: 0.28; 95% CI: 0.08 – 0.93; p=0.038), early primary tumor (HR: 0.52; 95% CI 0.30 – 0.89; p=0.017) and absence of distant metastasis (HR=0.15 95% CI: 0.07 – 0.3; p<0.001) were associated with lower risk of death from any causes after controlling other confounding factors. Most importantly, high TIL level in HPV-associated OPSCC patients was associated with 89% (HR: 0.11; 95% CI: 0.02 – 0.61; p=0.012) lower risk of death from any causes than those with low TIL level, but not present in non-HPV counterpart. In addition, either HPV PCR complemented with typical high-risk genotyping results or p16 IHC positivity complemented with HPC PCR positivity using specific designed primers were two reasonably sensitive and specific detection algorithms based on the local genotypic distribution of this disease. In summary, this is the first most comprehensive and robust local study indicating the importance of HPV-associated OPSCC in Hong Kong. It successfully illustrated various distinctive characteristics of this viral-related cancer. Additionally, it has suggested a potential predictor to identify the minority with more aggressive diseases and the most effective laboratory detection algorithms in this locality. It definitely facilitates the next step in exploring this disease via larger and prospective trials in coming future. / published_or_final_version / Surgery / Master / Master of Medical Sciences

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

In normal cells, the p53 tumour suppressor induces cell cycle arrest or apoptosis in response to a variety of stresses, including DNA damage and ectopic oncogene expression. However, cellular pathways controlled by p53 are compromised in virtually all cancers. Defining the mechanisms regulating p53 activity in normal and tumour cells has therefore been a major priority in cell biology and cancer research. / In this study, we characterized two important regulatory mechanims of p53 activity: (i) Human papillomavirus (HPV) E6 interaction and (ii) alternative splicing. Recognized as the major etiological agents for cervical cancer, the oncogenic potential of HPVs correlates with their ability to target p53 for degradation. This study demonstrates that both p53 and HPV-18 E6 are exported from the nucleus when co-expressed, via a process that involves the C-terminal nuclear export signal (NES) of p53. However, neither nuclear export nor the p53 C-terminal NES is required for HPV-18 E6-mediated ubiquitination or degradation of p53. / This study also demonstrates that both low- and high-risk HPV E6 proteins are degraded by the ubiquitin-proteasome pathway, and thus provides an explanation for the low levels of E6 detected in cervical cancer cells. / Also reported in this study is a novel mechanism of p53 regulation arising through alternative splicing. This novel mRNA encodes a N-terminal deleted isoform of p53, termed p47. As demonstrated within, p47 does not supress cell viability but impairs both p53-mediated transcriptional activity and growth suppression. Interestingly, p47 increases both p53 monoubiquitination and nuclear export. We propose that p47 induces nuclear export of p53 by a mechanism involving monoubiquitination, as supported by recent findings from Li and colleagues (2003). The p47 protein also protects p53 from both Mdm2- and HPV-18 E6-mediated degradation. A number of cancers display abnormal localization of wildtype p53, and it will be important to examine the role of p47 in these tumours. / Taken together, the regulation of p53 activity by both HPV E6 and the alternative splice variant p47 involves alterations in p53 ubiquitination status, protein stability, and cell localization. Insight gained into these negative regulatory mechanisms may aid in the design of therapeutic strategies for reactivating wild-type p53 in HPV-associated and non-associated cancers.

CD21 is a transmembrane receptor molecule, previously known as the CR2, C3d or EBV receptor, which was originally identified and characterized on the B-cell lymphoid series. It has also been described in various squamous cells but these reports are diverse and sometimes conflicting. This thesis is a study of putative CD21 on the squamous cells of the human cervix uteri. The introduction provides background information on the cervix and on CD21 and indicates lines of investigation followed later. Experimental studies commence with an immunohistochemical study in which a panel of anti-CD21 monoclonal antibodies was applied to fresh frozen sections of the cervix. Only one antibody, HB5 reacted positively and this was consistent. HB5 located to the cell membrane of normal squamous ectocervical cells in a band-like manner, above the basal layers and beneath the superficial layers. Significantly HB5 did not react with CIN or koilocytes. That only HB5 reacted was subsequently confirmed by flow cytometry. That it reacted only with cell membrane was confirmed by confocal laser microscopy. Further, the lower limit of the HB5 positive band was confirmed by a dual labeling study employing HB5 and MIB-1 which recognizes cycling cells. Cells labeled with these antibodies appear mutually exclusive. Cycling cells in vivo are not HB5 positive. Western blotting studies on extracts of normal cervical epithelium indicated that HB5 reacted with a molecule larger than that found on lymphoid cells. However, they do share the same epitope. Having demonstrated an HB5 epitope on epithelial cells which were not cycling but were not yet fully differentiated, a series of in vitro experiments were conducted to see if the epitope was functional in a receptor sense, or was an epiphenomenon. Monolayer cultures, with appropriate controls, were exposed to HB5. Small effects were demonstrated in thymidine incorporation, protein synthesis and cell numbers, in early culture stages. The concluding general discussion gives some thought to the possible role of maturation in the control of neoplasia.

Thesis (M. Med. Sc.)--University of Hong Kong, 2007.

Thesis (Ph. D.)--University of Hong Kong, 1998. / Includes bibliographical references (leaf 147-169).

Thesis (Ph.D.)--Georgetown University, 2009. / Includes bibliographical references.