Genetic epidemiology of cell division regulation in breast cancer

描述（由申请人提供）：与染色体不稳定性相关的非整倍性和多倍性是许多乳腺癌的标志，并被认为是肿瘤形成的最早阶段。最近的证据已经确定，非整倍体/多倍体甚至可能导致乳腺癌。虽然已经知道了很多关于导致非整倍体/多倍体的分子机制，但在遗传和流行病学水平上了解甚少。我们推测，参与调节细胞分裂的基因的遗传变异有助于非整倍体/多倍体的发展，并随后导致乳腺癌。我们提出了一个全面的多阶段的方法来研究基因参与调节细胞分裂使用单一的变体和单倍型。我们将在马约诊所乳腺癌病例对照研究中确定与乳腺癌风险相关的候选变异和单倍型，并在英国圣公会乳腺癌（ABC）研究中验证相关性。将对含有变异体的基因进行重新测序，并在扩展的马约诊所乳腺癌研究中选择代表小单倍型块的单倍型标记变异体并进行重新基因分型，以鉴定与乳腺癌风险相关的特定变异体或单倍型块。这些变体和单倍型将在扩展的ABC研究中进行验证，并表征这些SNP对基因表达和功能的影响。我们的具体目标是：目标一：确定并确认调节细胞分裂的基因中单核苷酸多态性（SNP）和单倍型与乳腺癌风险之间的关联。具体目标#2：描述马约诊所乳腺癌研究人群中与乳腺癌风险相关的基因中的所有遗传变异。具体目标#3：确定这些基因中导致癌症风险改变的变异。具体目标#4：描述与乳腺癌风险相关的有丝分裂调控基因遗传变异的功能意义。这项研究将解决乳腺癌病因的细胞分裂调节的不足评估领域的贡献。该研究将超越风险标志物的识别，以表征实际导致乳腺癌风险改变的变异。这些结果将为改善风险评估提供信息，并可能为乳腺癌预防和治疗药物提供靶点。

DESCRIPTION (provided by applicant): Aneuploidy and polyploidy associated with chromosomal instability are hallmarks of many breast cancers and have been implicated as some of the earliest steps in tumor formation. Recent evidence has established that aneuploidy/polyploidy can even predispose to breast cancer. While much is already known about the molecular mechanisms leading to aneuploidy/polyploidy, little is understood at the genetic and epidemiological level. We hypothesize that inherited variation in genes involved in regulating cell division contribute to the development of aneuploidy/polyploidy and subsequently to breast cancer. We propose a comprehensive multi stage approach to the study of genes involved in regulation of cell division using single variants and haplotypes. We will identify candidate variants and haplotypes associated with breast cancer risk in the Mayo Clinic Breast Cancer case-control Study and validate the associations in the Anglican Breast Cancer (ABC) Study. The genes containing the variants will be resequenced and haplotyped tagging variants representing small haplotype blocks will be selected and re-genotyped in an expanded Mayo Clinic Breast Cancer Study to identify the specific variants or haplotype blocks that account for the association with breast cancer risk. These variants and haplotypes will be validated in an expanded ABC study and the influence of these SNPs on gene expression and function will be characterized. Our specific aims are: Aim #1: To identify and confirm associations between Single Nucleotide Polymorphisms (SNPs) and haplotypes in genes that regulate cell division and breast cancer risk. Specific Aim #2: To characterize all genetic variation in the genes displaying association with breast cancer risk in the Mayo Clinic Breast Cancer Study population. Specific Aim #3: To identify the variants in these genes that account for the modified risk of cancer. Specific Aim #4: To characterize the functional significance of inherited variation in mitotic regulation genes that is associated with breast cancer risk. This study will address the contribution of the under-evaluated area of regulation of cell division to breast cancer etiology. The study will go beyond identification of risk markers to the characterization of the variants that actually cause the modification of breast cancer risk. The results will provide information for improved risk assessment and could provide targets for breast cancer prevention and therapeutic agents.