COMMON AND RARE SEQUENCE VARIANTS IN BREAST CANCER RISK

描述（由申请人提供）：结合分离分析和突变筛选研究的数据，已确定的乳腺癌易感基因约占该疾病遗传成分的20%-25%。导致乳腺癌风险的其余遗传因素的基因和/或序列变异尚未确定。目前大多数对snp和单倍型图谱的热情都是基于一个假设，即常见的中等风险变异是最重要的。然而，常见snp与乳腺癌风险之间的候选关联很少被独立再现。因此，本研究的核心问题是：常见（通常是中等风险）序列变异与罕见（潜在高风险）序列变异对乳腺癌遗传归因部分的相对贡献是什么？使用1250例不同种族的遗传高危乳腺癌病例和1250例频率匹配的人群对照，我们提出了一项新的研究，旨在直接比较常见病/常见变异和常见病/罕见变异的遗传易感性模型。这项研究分为两部分。首先，我们将用已知的或乳腺癌遗传学研究团体在本研究过程中发现的所有常见序列变异对病例和对照进行基因分型，以预测乳腺癌风险的增加。在第二组中，我们将在病例和对照组中对强候选易感基因的开放阅读框进行突变筛选。基因型和突变筛选数据的分析应该为研究的中心问题提供答案。与没有这些标准的类似规模的研究相比，我们对早期发病和家族性病例的关注将大大提高检测有害序列变异所带来的风险的能力。fl本研究的结果在三个方面与公共卫生相关：(1)本研究将提供基因及其突变的假设检验，这些基因和突变似乎会使乳腺癌的风险适度到急剧增加。测量由这些基因突变引起的风险是关键的一步，它介于基因在乳腺癌易感性中起作用的最初迹象和将基因带入癌症遗传学的临床实践之间。(2)本研究结果将对未来临床癌症遗传学研究方向产生影响。中等风险与中等风险序列变异对乳腺癌归因风险的相对贡献将对遗传信息如何进入临床实践产生影响。(3)分析基因型和突变筛选数据，比较常见变异和罕见变异的癌症易感性遗传模型的风险。这是目前遗传学研究界最感兴趣和重要的问题。如果我们观察到罕见的序列变异与常见的snp一样多或更多的风险，那么可能有必要将突变筛查从遗传流行病学/家族研究领域扩展到更大规模的基于人群的研究。

DESCRIPTION (provided by applicant): Combining data from segregation analyses and mutation screening studies, the established breast cancer susceptibility genes are responsible for an estimated 20%-25% of the genetic component of this disease. The genes and/or sequence variants responsible for the remaining genetic component of breast cancer risk have yet to be identified. Most of the current enthusiasm for SNPs and haplotype mapping are predicated on the assumption that common modest risk variants are most important. However, few candidate associations between common SNPs and breast cancer risk have been independently reproduced. Thus the central question of this study: What is the relative contribution of common (usually modest-risk) sequence variants vs. rare (potentially higher-risk) sequence variants to the genetic attributable fraction of breast cancer? U Using an ethnically diverse series of 1,250 genetically high-risk breast cancer cases and 1,250 frequency-matched population controls, we propose a novel study designed to make a direct comparison between the common disease/ common variant and common disease/ rare variant models of genetic susceptibility. The study has two arms. In the first, we will genotype the cases and controls with all of the common- sequence variants that are known, or are found over the course of this study by the breast cancer genetics research community, to predict increased risk of breast cancer. In the second arm, we will mutation screen the open reading frames of strong candidate susceptibility genes in both the cases and the controls. Analysis of the genotype and mutation screening data should provide an answer to the central study question. Our focus on early onset and familial cases will substantially increase power to detect risk conferred by deleterious sequence variants as compared to a study of similar size without these criteria, fl Results from this study are relevant to public health in three ways: (1) This study will provide a hypothesis test of genes, and mutations in them, that appear to confer moderately to dramatically increased risk of breast cancer. Measuring risk due to mutations in these genes is a key step that lies between initial indications that the gene plays a role in breast cancer susceptibility and bringing the gene into the clinical practice of cancer genetics. (2) Results from this study will bear on the future direction of clinical cancer genetics. The relative contribution that moderate risk versus modest risk sequence variants make to the attributable risk of breast cancer will have an impact on how the genetic information enters clinical practice. (3) Analysis of the genotype and mutation screening data will provide a comparison of risk attributable to the common variant and rare variant genetic models of cancer susceptibility. This is a question of major current interest and importance within the genetics research community. If we observe that the rare sequence variants account for as much or more risk than do common SNPs, it may be necessary to expand mutation screening from the realm of genetic epidemiology/ family studies into larger scale population-based studies.