published_or_final_version / Nursing Studies / Master / Master of Nursing in Advanced Practice

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Nursing Studies / Master / Master of Nursing in Advanced Practice

Breast cancer is the most common cancer in women in most part of the world. Although there are multiple risk factors which have been reported to be related to breast factors, by far one of the highest risk of breast cancer is the inheritance of the BRCA1 and BRCA2 cancer susceptibility genes. The lifetime risk of breast cancer can be as high as 60-80% for BRCA mutation carriers. As the breast cancer epidemiology and genetic predisposition is increasingly understood, it transpires that ethnic differences exist. Although variations of genetic factors may play a role, the reasons for these differences remain unclear. Most published data are Caucasian based and there are limited publications on hereditary breast cancer in Asians available to date. This thesis hypothesizes that due to the known differences in genetic predisposition in different ethnic groups, it is likely that the mutation spectrum of BRCA mutations and breast cancer characteristics of Hong Kong Chinese, a relatively unexplored cohort, will differ to that of Caucasians. Moreover, the ancestors of local Hong Kong population migrated from Mainland China of which majority were from Southern China. They then remained in Hong Kong and populated and hence similar to smaller countries such as Iceland and Poland where founder mutations are identified, it is likely that a founder mutation will be present. Lastly due to different cultural differences and availability of screening facilities, management options of those found to carry the BRCA mutation may differ to that of other countries. The aims of this study are as follows 1) Perform a comprehensive genetic and phenotypic analysis using Full Gene Sequencing and Multiplex ligation-dependent probe amplification (MLPA) testing of Hong Kong Chinese cohort or breast cancer patients/families who are clinically high risk and to develop a registry to collect data related to this study. 2) To identify the spectrum of BRCA mutation in Hong Kong. 3) To report, any novel mutations, founder mutations, large rearrangements and deletions (using MLPA) if any are found. 4) If founder mutations are present, to develop a fasting and cheaper technique so that rapid screening can be offered. 5) To identify the choice of management in this high risk cohort. A total of 451 clinically high-risk breast and /or ovarian cancer patients from 1 March 2007 to 28 February 2011 were recruited. Based on sequencing results, 59 (13.1%) deleterious BRCA gene mutations were identified: 24 (41%) were in BRCA1 and 35 (59%) in BRCA2. Of the 59 deleterious mutations, 22 (37%) were novel mutations, 8 were BRCA1 and 14 were BRCA2 mutations. Eight recurrent mutations were identified of which four were proven to be founder mutations. These results showed that both BRCA1 and BRCA2 mutations account for a substantial proportion of hereditary breast/ovarian cancer in Sothern Chinese population. By using MLPA, four patients with large genomic rearrangement were identified and one of whom has a de novo BRCA1 mutation encompassing exons 1 to 12 deletion. Such mutations are rare and this de novo mutation has not been previously reported. Moreover another novel BRCA2 variant of unknown significance (c.7806-9T>G), a splice-site intronic mutation, was recharacterized to be pathogenic due to clinical suspicion based on its co-segregation. High Resolution Melting Technique in performing rapid screening for the founder mutations was developed and tested on a further cohort confirming the possibility of the use of founder mutations screening technique in future. Finally, concerning the management choice of BRCA mutation carriers undertaken in Chinese, BRCA mutation carriers in our cohort are more likely to choose intensive surveillance as an option of risk management rather than prophylactic interventions. In summary, this study provides valuable information on mutation spectrum of BRCA1 and BRCA2 in Southern Chinese population. Identifications founder mutations and knowledge of its prevalence in this Chinese population provides important information both to genetic counselling and risk assessment as well as to development of a cost-effective screening strategy. Furthermore, our study on the choice of management of mutation carriers allows us to have a baseline for development of future studies of psychological impact of genetic testing and management related to genetic testing, so that these high risk families can be better supported. / published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

published_or_final_version / Social Work and Social Administration / Master / Master of Social Sciences

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / abstract / toc / Clinical Psychology / Master / Master of Social Sciences

Increasing number of people is diagnosed with colorectal neoplasms (CRN) in the form of polyps or cancers. Colorectal cancer (CRC) is one of the most common causes of cancer deaths among Chinese in Hong Kong. Advances in diagnosis and treatments have increased the survival rate of CRN patients, resulting in a large group of cancer survivors. Preserving and maintaining health-related quality of life (HRQOL) has become an important direction in research and clinical care of patients with CRN. This research aimed to evaluate the HRQOL and its association with socio-demographics and disease-related characteristics among patients with CRN, and illustrate how HRQOL data could be converted to preference for the estimation of quality adjustment of life years in health economic evaluations. This research comprised of three parts. First was the establishment of the validity and reliability of the traditional Chinese version of Functional Assessment of Cancer Therapy-Colorectal (FACT-C) as a HRQOL measure for Chinese patients by a cross-sectional sample of 536 adult patients with CRN. Psychometric testing and concurrent validation of the FACT-C with European Organization for Research and Treatment of Cancer Core Questionnaire plus Colorectal-specific Module Questionnaire and the Short-Form 12-item Health Survey_Version2 (SF-12V2) were carried out. Second was a longitudinal study on the HRQOL of 554 CRN patients at baseline, six (n=479) and twelve (n=414) months of recruitment. The associations of HRQOL with socio-demographics and disease-related factors, and change of HRQOL over time were explored. Comparisons of HRQOL between CRN patients and the general population and among different CRN groups were made. Cross-sectional data were used to develop mapping functions to estimate SF-6D preference scores from FACT-C subscale scores. Third was the application of the health preference scores by CRN stages collected at baseline of the longitudinal study, in combination with survival data extracted from the literature in a Markov model on the cost-effectiveness of different CRC screening strategies (colonoscopy, guaiac and immunochemical fecal occult blood tests) in comparison to no screening in terms of quality-adjusted life-years gained. This research comprised of three parts. First was the establishment of the validity and reliability of the traditional Chinese version of Functional Assessment of Cancer Therapy-Colorectal (FACT-C) as a HRQOL measure for Chinese patients by a cross-sectional sample of 536 adult patients with CRN. Psychometric testing and concurrent validation of the FACT-C with European Organization for Research and Treatment of Cancer Core Questionnaire plus Colorectal-specific Module Questionnaire and the Short-Form 12-item Health Survey_Version2 (SF-12V2) were carried out. Second was a longitudinal study on the HRQOL of 554 CRN patients at baseline, six (n=479) and twelve (n=414) months of recruitment. The associations of HRQOL with socio-demographics and disease-related factors, and change of HRQOL over time were explored. Comparisons of HRQOL between CRN patients and the general population and among different CRN groups were made. Cross-sectional data were used to develop mapping functions to estimate SF-6D preference scores from FACT-C subscale scores. Third was the application of the health preference scores by CRN stages collected at baseline of the longitudinal study, in combination with survival data extracted from the literature in a Markov model on the cost-effectiveness of different CRC screening strategies (colonoscopy, guaiac and immunochemical fecal occult blood tests) in comparison to no screening in terms of quality-adjusted life-years gained. Psychometric analysis confirmed that FACT-C had satisfactory reliability, construct validity and responsiveness in Chinese patients Patients with CRN reported worse physical HRQOL but better mental HRQOL and similar health preference score compared to the general population. Disease severity indicated by tumor stage at initial diagnosis was the most significant determinant of HRQOL of CRN patients. Rectal cancer also significantly associated with a decrease in physical HRQOL and health preference scores. Markov modelling showed that immunochemical fecal occult blood (I-FOBT) yearly was the most effective and two-yearly was the most cost-effective screening strategy compared to no screening. / published_or_final_version / Family Medicine and Primary Care / Doctoral / Doctor of Philosophy

published_or_final_version / Social Work / Master / Master of Social Work

published_or_final_version / Social Work and Social Administration / Doctoral / Doctor of Philosophy