published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

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published_or_final_version / abstract / Surgery / Master / Master of Philosophy

Head and neck cancers account for 3% of all newly diagnosed cancers, of which 90% are squamous cell carcinomas (SCC). Improvements in surgery, radiotherapy and chemotherapy have done little to improve the mortality of this disease over the past 20 years while current clinicopathological predictors of disease outcome are sub-optimal. Identifying molecular targets of prognostic and therapeutic significance in head and neck squamous cell carcinomas (HNSCC) may help direct novel therapies to patients whom it is most likely to benefit. Accrued knowledge of the biology of HNSCC has highlighted specific aberrations in pRb and p53 pathways which warrant further study. An immunohistochemical analysis (IHC) in a cohort of 145 patients with SCC of the anterior tongue was performed. Protein expression of the pRb and p53 pathways and related molecules that directly or indirectly influence cell cycle progression at the G1/S phase checkpoint was assessed. We determined that over-expression of E2F-1 occurred in &gt35% of these cancers and associated with improved overall survival on univariate analysis. The strongest multivariate model included: regional lymph node status, tumour grade, p16INK4A, cyclin D1 and p14ARF. This is the first study to determine that p14ARF is an independent marker of both improved diseasefree survival and overall survival in a cohort of SCC of the anterior tongue. Unrecognized molecular heterogeneity is thought to account for the unpredictable clinical response to ZD1839, an EGFR tyrosine kinase inhibitor. We explored the anti-proliferative effects following ZD1839 treatment alone or in combination with radiotherapy in cyclin D1 and E2F-1 over-expressing SCC9 HNSCC cells. SCC9 cells over-expressing cyclin D1 or E2F-1 were highly resistant to ZD1839 treatment, while E2F-1 clones were also radioresistant. Combined therapy in SCC9 controls had a greater anti-proliferative effect than each individual treatment. These data showed that cyclin D1 and E2F-1 may have utility as markers of ZD1839 resistance. The data in this thesis contribute to our knowledge of the clinical behaviour and molecular pathology of HNSCC. Specifically the molecular data identifies novel markers of outcome in SCC of the anterior tongue such as p14ARF, and therapeutic response to ZD1839 such as cyclin D1 and E2F-1. This study addresses in part, the current issues and limitations of management in HNSCC and has the potential to contribute to strategies that may be developed to improve the outcome for patients who develop HNSCC in the future.

Cervical cancer is a common gynaecological malignancy worldwide, with more than 450,000 incidences every year. Its etiology has been well documented to be associated with persistent infection with high-risk genotypes of human papillomavirus (HPV). The carcinoma can be screened by convention Pap smear and liquid-based cytology. Although preventable, cervical cancer remains a primary cause of death from cancer in developing countries where cytological screening is not so available. In the past decades, many studies have been carried out to explore molecular screening or diagnosis of cervical cancer, such as HPV DNA testing, histological or cytological biomarkers. Micro RNAs, small non-coding RNA molecules of 18-25 nucleotides in length, areaberrantly expressed in various cancers. MiR-143 was reported consistently downregulated in cervical cancer tissues and cell lines, but its functional roles in cervical carcinogenesis has not been clearly illustrated. Ten miR-143 downstream target genes were chosen and their expression levels in five cervical cancer cell lines (HeLa, SiHa, CaSki, C4-I and C33A) were investigated. In general, the gene expressions of candidates are upregulated in our cell lines with lowmiR-143 level. To further identify specific miR-143 targets in cervical cancer for biomarkers, protein expressions of TARDBP, ERK5, KRAS and PHF6were significantly downregulated upon miR-143 overexpression. Hence, miR-143 level is inversely correlated with the mRNA and protein expressions of these target genes. Immunohistochemical study of ERK5 and TARDBP on FFPE samples including normal cervix, CINs and SCC cases showed that both ERK5 and TARDBP were positively stained in SCC samples, whereas weaker staining was found in CINs (both LSILs and HSILs) for both antigens. Thus, the intensity of positive staining ascended with the histological grading: LSIL, HSIL and SCC samples. Such differential expression pattern supports ERK5 and TARDBP as specific markers for high grade cancerous lesions. In summary, two targets of miR-143, ERK5 and TARDBP, could be specific markers for high-grade lesion of cervical cancer. This is supported by their transcript and protein expressions inversely associated with miR-143 level, and that their strong immunohistochemical positivity in SCC samples. Their underlying molecular mechanisms involved in carcinogenesis and possible future applications require more in-depth researches. / published_or_final_version / Pathology / Master / Master of Medical Sciences

Head and neck cancers account for 3% of all newly diagnosed cancers, of which 90% are squamous cell carcinomas (SCC). Improvements in surgery, radiotherapy and chemotherapy have done little to improve the mortality of this disease over the past 20 years while current clinicopathological predictors of disease outcome are sub-optimal. Identifying molecular targets of prognostic and therapeutic significance in head and neck squamous cell carcinomas (HNSCC) may help direct novel therapies to patients whom it is most likely to benefit. Accrued knowledge of the biology of HNSCC has highlighted specific aberrations in pRb and p53 pathways which warrant further study. An immunohistochemical analysis (IHC) in a cohort of 145 patients with SCC of the anterior tongue was performed. Protein expression of the pRb and p53 pathways and related molecules that directly or indirectly influence cell cycle progression at the G1/S phase checkpoint was assessed. We determined that over-expression of E2F-1 occurred in &gt35% of these cancers and associated with improved overall survival on univariate analysis. The strongest multivariate model included: regional lymph node status, tumour grade, p16INK4A, cyclin D1 and p14ARF. This is the first study to determine that p14ARF is an independent marker of both improved diseasefree survival and overall survival in a cohort of SCC of the anterior tongue. Unrecognized molecular heterogeneity is thought to account for the unpredictable clinical response to ZD1839, an EGFR tyrosine kinase inhibitor. We explored the anti-proliferative effects following ZD1839 treatment alone or in combination with radiotherapy in cyclin D1 and E2F-1 over-expressing SCC9 HNSCC cells. SCC9 cells over-expressing cyclin D1 or E2F-1 were highly resistant to ZD1839 treatment, while E2F-1 clones were also radioresistant. Combined therapy in SCC9 controls had a greater anti-proliferative effect than each individual treatment. These data showed that cyclin D1 and E2F-1 may have utility as markers of ZD1839 resistance. The data in this thesis contribute to our knowledge of the clinical behaviour and molecular pathology of HNSCC. Specifically the molecular data identifies novel markers of outcome in SCC of the anterior tongue such as p14ARF, and therapeutic response to ZD1839 such as cyclin D1 and E2F-1. This study addresses in part, the current issues and limitations of management in HNSCC and has the potential to contribute to strategies that may be developed to improve the outcome for patients who develop HNSCC in the future.

Head and neck cancers account for 3% of all newly diagnosed cancers, of which 90% are squamous cell carcinomas (SCC). Improvements in surgery, radiotherapy and chemotherapy have done little to improve the mortality of this disease over the past 20 years while current clinicopathological predictors of disease outcome are sub-optimal. Identifying molecular targets of prognostic and therapeutic significance in head and neck squamous cell carcinomas (HNSCC) may help direct novel therapies to patients whom it is most likely to benefit. Accrued knowledge of the biology of HNSCC has highlighted specific aberrations in pRb and p53 pathways which warrant further study. An immunohistochemical analysis (IHC) in a cohort of 145 patients with SCC of the anterior tongue was performed. Protein expression of the pRb and p53 pathways and related molecules that directly or indirectly influence cell cycle progression at the G1/S phase checkpoint was assessed. We determined that over-expression of E2F-1 occurred in &gt35% of these cancers and associated with improved overall survival on univariate analysis. The strongest multivariate model included: regional lymph node status, tumour grade, p16INK4A, cyclin D1 and p14ARF. This is the first study to determine that p14ARF is an independent marker of both improved diseasefree survival and overall survival in a cohort of SCC of the anterior tongue. Unrecognized molecular heterogeneity is thought to account for the unpredictable clinical response to ZD1839, an EGFR tyrosine kinase inhibitor. We explored the anti-proliferative effects following ZD1839 treatment alone or in combination with radiotherapy in cyclin D1 and E2F-1 over-expressing SCC9 HNSCC cells. SCC9 cells over-expressing cyclin D1 or E2F-1 were highly resistant to ZD1839 treatment, while E2F-1 clones were also radioresistant. Combined therapy in SCC9 controls had a greater anti-proliferative effect than each individual treatment. These data showed that cyclin D1 and E2F-1 may have utility as markers of ZD1839 resistance. The data in this thesis contribute to our knowledge of the clinical behaviour and molecular pathology of HNSCC. Specifically the molecular data identifies novel markers of outcome in SCC of the anterior tongue such as p14ARF, and therapeutic response to ZD1839 such as cyclin D1 and E2F-1. This study addresses in part, the current issues and limitations of management in HNSCC and has the potential to contribute to strategies that may be developed to improve the outcome for patients who develop HNSCC in the future.

Includes bibliographies. / [xvii], 173, [38] leaves, [18] leaves of plates : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / This thesis presents the development of an assay for reverse transcription-polymerase chain reaction (RT-PCR) to be applied to the immunomagnetic isolation of carcinoma cells, as a possible means of detecting small numbers of breast cancer cells in a haemopoietic environment. The messenger RNA expression of two different genes, CD44 and the cytokeratin K19, is assessed for suitability as tumour markers for the Immunobead RT-PCR method, and clinical results using K19 are presented. / Thesis (M.D.)--University of Adelaide, Dept. of Medicine, 1977?

published_or_final_version / Pathology / Master / Master of Medical Sciences

published_or_final_version / Pathology / Doctoral / Doctor of Philosophy