Cell Cycle/Apoptosis Gene Variants and Breast Cancer Risk

描述(由申请人提供)：众所周知，遗传因素在乳腺肿瘤的发生中起着重要作用。然而，已知的乳腺癌易感基因只占普通人群乳腺癌病例的一小部分。来自体外和动物研究的累积证据表明，参与细胞周期控制和凋亡途径的基因可能与乳腺癌有关。细胞周期调控和细胞凋亡途径作为一个完整的分子网络发挥作用，其中一个途径的扰动可以对另一个途径产生深远的影响。在这一应用中，我们建议调查与乳腺癌风险相关的细胞周期控制和细胞凋亡途径中主要基因的遗传变异。这项拟议的研究将使用上海乳腺癌研究(SBCS，R01CA64277)收集的数据和生物样本。在1996年至1998年招募的1250例病例和1250例对照中，最初将使用基因型和单倍型方法来评估细胞周期控制和凋亡途径中25个候选基因的遗传多态。在最初阶段确定的有希望的关联将在2002年至2005年招募的第二组受试者(1850例病例和1850例对照)中重新评估。这种两阶段的研究设计将有效地平衡I型和II型统计错误，并为我们理解乳腺癌的病因提供可信的结果。我们将使用多因素降维(MDR)统计方法来研究任何与乳腺癌风险相关的基因-基因交互作用。我们将研究基因多态与内源性雌激素暴露相关因素之间的相互作用与乳腺癌风险的关系。我们将评估基因多态是否可能与特定亚型乳腺癌的风险相关。我们还将进行体外实验，以评估遗传变异的功能，以进一步证实这种联系的生物学相关性。由于其庞大的规模和强大的方法学，SBCS为研究与乳腺癌风险相关的基因-基因和基因-环境相互作用提供了一个很好的机会。这项拟议研究的结果可能会极大地提高我们对乳腺癌病因的认识，并将对识别乳腺癌一级和二级预防的高危妇女有价值。 我们建议研究参与细胞周期控制和细胞凋亡途径的主要基因的遗传变异与乳腺癌风险的关系。这项拟议研究的结果可能会极大地提高我们对乳腺癌病因的认识，并将对识别乳腺癌一级和二级预防的高危妇女有价值。

DESCRIPTION (provided by applicant): It is well established that genetic factors play a major role in breast tumorigenesis. However, the known breast cancer susceptibility genes account for only a minority of breast cancer cases in the general population. Cumulative evidence from in vitro and animal studies suggests that the genes involved in the cell-cycle control and apoptosis pathways may be related to breast cancer. The cell-cycle control and apoptosis pathways function as an integrated molecular network, and perturbations in one pathway can have profound consequences on the other. In this application, we propose to investigate genetic variations of major genes involved in the cell- cycle control and apoptosis pathways in relation to breast cancer risk. The proposed study will use data and biological samples collected from the Shanghai Breast Cancer Study (SBCS, R01CA64277). Genetic polymorphisms in 25 candidate genes in the cell-cycle control and apoptosis pathways will initially be evaluated using both the genotype- and haplotype- approaches in 1,250 cases and 1,250 controls recruited from 1996 to 1998. Promising associations identified in the initial phase will be re-evaluated in a second set of subjects (1,850 cases and 1,850 controls) recruited from 2002 to 2005. This two-phase study design will effectively balance both Type I and Type 2 statistical errors and provide credible results towards our understanding of the etiology of breast cancer. We will use the multifactor-dimensionality reduction (MDR) statistical method to investigate any gene-gene interaction in relation to breast cancer risk. We will investigate interaction between genetic polymorphisms with endogenous estrogen exposure related factors in relation to breast cancer risk. We will evaluate whether genetic polymorphisms may be associated with the risk of specific subtypes of breast cancer. We will also conduct in vitro experiments to evaluate the function of genetic variations to further confirm the biological relevance of the association. With its large size and strong methodology, the SBCS provides a great opportunity to investigate gene-gene and gene-environment interactions in relation to breast cancer risk. The findings from the proposed study are likely to significantly advance our knowledge of the etiology of breast cancer and will be valuable for identifying high risk women for the primary and secondary prevention of breast cancer. We propose to investigate genetic variations of major genes involved in the cell-cycle control and apoptosis pathways in relation to breast cancer risk. The findings from the proposed study are likely to significantly advance our knowledge of the etiology of breast cancer and will be valuable for identifying high risk women for the primary and secondary prevention of breast cancer.