COMMON AND RARE SEQUENCE VARIANTS IN BREAST CANCER RISK

乳腺癌风险中常见和罕见的序列变异

• 批准号: 7891415
• 负责人: Sean Vahram Tavtigian
• 金额: $ 45.94万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7891415
• 关键词: Accounting; Address; Affect; Age; Alleles; BRCA1 gene; BRCA2 gene; Breast Cancer Genetics; Cancer-Predisposing Gene; Case Series; Case-Control Studies; Clinical; Code; Communities; Complex; Computational Biology; Data; Data Analyses; Diagnosis; Disease; Ethnic Origin; Exons; Family; Family Study; Family history of; Flowcharts; Frequencies; Future; Gene Mutation; Gene Targeting; Genealogy; Genes; Genetic; Genetic Models for Cancer; Genetic Predisposition to Disease; Genetic Research; Genetic Risk; Genomics; Genotype; Goals; Haplotypes; Individual; Inherited; Link; Mammary Neoplasms; Maps; Measures; Modeling; Mutation; Open Reading Frames; Play; Population; Population Attributable Risks; Population Control; Population Genetics; Predisposition; Process; Public Health; Publications; RNA Splicing; Rare Diseases; Relative (related person); Research Design; Research Personnel; Resolution; Resources; Risk; Role; SNP genotyping; Sampling; Scanning; Screening procedure; Sequence Alignment; Series; Splice-Site Mutation; Stratification; Susceptibility Gene; Testing; Twin Studies; Ursidae Family; Variant; Woman; Work; arm; base; cancer genetics; cancer risk; case control; clinical practice; early onset; gene discovery; gene function; genetic epidemiology; genetic pedigree; high risk; interest; malignant breast neoplasm; melting; neoplasm registry; novel; novel strategies; population based; programs; segregation

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.

描述（由申请人提供）：结合了分离分析和突变筛查研究的数据，已建立的乳腺癌易感基因估计是该疾病遗传成分的20％-25％。负责乳腺癌剩余遗传成分的基因和/或序列变体尚未确定。当前对SNP和单倍型映射的热情是基于以下假设：普通谦虚的风险变体是最重要的。但是，普通SNP与乳腺癌风险之间的候选人关联很少被独立再现。因此，这项研究的中心问题是：与罕见（潜在的高风险）序列变体相对于乳腺癌的遗传归因分数，常见（通常是中等风险）序列变体的相对贡献是什么？ U使用种族多样化的1,250个遗传性高危乳腺癌病例和1,250个频率匹配的人群对照系列，我们提出了一项新型研究，旨在直接比较常见疾病/常见变异和常见疾病/稀有疾病/稀有遗传敏感性模型。该研究有两个臂。首先，我们将与乳腺癌遗传学研究界在本研究过程中发现或在本研究过程中发现的所有常见序列变体的病例和对照，以预测乳腺癌的风险增加。在第二组中，我们将在病例和对照组中突变屏幕强候选敏感性基因的开放阅读框。对基因型和突变筛选数据的分析应为中心研究问题提供答案。与没有这些标准的相似大小的研究相比，我们对早期发作和家族病例的关注将大大提高有害序列变体赋予的风险的能力，这项研究的FL结果与公共卫生有关：（1）这项研究将提供对基因的假设测试，以及其中的突变，似乎会增加术语的风险，从而使乳腺癌的风险有所增加。测量这些基因突变引起的风险是一个关键步骤，它在最初的迹象表明该基因在乳腺癌敏感性中起作用并将基因带入癌症遗传学的临床实践。 （2）这项研究的结果将遵循临床癌遗传学的未来方向。中等风险与中等风险序列变体对乳腺癌的归因风险所产生的相对贡献将对遗传信息进入临床实践的方式产生影响。 （3）对基因型和突变筛查数据的分析将提供可归因于癌症易感性的常见变体和罕见变体遗传模型的风险。这是遗传学研究界的当前主要兴趣和重要性的问题。如果我们观察到罕见的序列变体比普通SNP所占的风险或更多的风险，则可能有必要将突变筛查从遗传流行病学/家庭研究领域扩展到基于大规模的人群研究中。