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This dissertation, Genetic Polymorphism of BRCA2 Minor Variant in Breast Cancer of Hong Kong Chinese Population by Janice, Wong, 黃正而, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Breast cancer is the leading malignancy among Asian women, which often have a young disease onset pattern. Germline mutation in high-penetrance breast cancer susceptibility genes are known to play an important role in early disease onset, but only 5-10% cases are associated with mutations in BRCA1 or BRCA2 gene. By contrast, common variants might also have deleterious effect in breast cancer development. A BRCA2 coding SNP rs1799944 (N991D) was found to have no association with breast cancer risk among Hong Kong Chinese population, but significantly confers a better disease-free survival in the breast cancer patients. In this study, the relevance of this association was further verified by using an enlarged sample pool of Hong Kong Chinese breast cancer patients. A total of 483 Hong Kong Chinese breast cancer subjects were unselectively recruited between 1976 and 2011. SNP N991D genotype of patients was determined by Taqman allelic discrimination genotyping assay. Pearson's Chi-Square and logistic regression were used to assess the association between the SNP genotypes and breast cancer disease characteristics. Kaplan-Meier survival and multivariate Cox proportional hazards regression analyses were used to examine the relationship between the SNP genotypes and overall survival as well as disease-specific survival of the patients. Of the 449 breast cancer patients successfully genotyped, 16.9% had heterozygous AG genotype and 0.4% had rare homozygotes GG genotype. The variant allele G had a MAF of 8.91% among Hong Kong Chinese breast cancer patients. Patients harboring the SNP N991D variant allele G had longer disease-free survival period compared to the non-carriers (HR = 0.28; 95% CI: 0.09 - 0.92; p=0.036), which was confounded by patients' local and/or distant metastasis status at diagnosis stage (HR=3.00; 95% CI: 1.57 - 5.74; p=0.001). Although N991D carriers also had a better overall survival pattern than the non-carriers, the difference between them was not statistically significant. Moreover, the association of SNP N991D variant allele G carriers with a lower disease recurrence rate (OR= 0.27; 95% CI: 0.82 - 0.90; p=0.023) was owing to the association of the variant with fewer distant metastases (OR = 0.11; 95% CI: 0.02 - 0.83; p=0.010) but not the local relapse status (OR= 0.38; 95% CI: 0.85 - 1.67; p=0.182) of the clinical outcome when comparing to the non-carriers. In conclusion, the missense BRCA2 N991D SNP has indicated an association with better clinical outcome as well as disease-free survival in Hong Kong Chinese breast cancers. DOI: 10.5353/th_b4854187 Subjects: Breast - Cancer - Genetic aspects - China - Hong Kong

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