published_or_final_version / abstract / Pathology / Master / Master of Philosophy

published_or_final_version / Pathology / Doctoral / Doctor of Philosophy

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

published_or_final_version / Pathology / Master / Master of Philosophy

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Pathology / Master / Master of Medical Sciences

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 / abstract / toc / Medicine / Master / Doctor of Medicine

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / abstract / toc / Surgery / Master / Master of Philosophy