Hereditary Breast Cancer and Novel Hispanic BRCA Mutations

遗传性乳腺癌和新型西班牙裔 BRCA 突变

• 批准号: 7664011
• 负责人: JEFFREY N WEITZEL
• 金额: $ 8.3万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7664011
• 关键词: Accounting; Admixture; Age; BRCA1 gene; Biological Assay; Blood; Cancer Etiology; Censuses; Cessation of life; Clinic; Clinical; Clinical Data; Comparative Study; DNA Sequence Rearrangement; Data; Databases; Development; Exons; Family; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Health; Hereditary Breast Carcinoma; Hispanics; Immigrant; Individual; Knowledge; Latino; Lead; Literature; Los Angeles; Malignant Neoplasms; Methods; Mexican; Mutation; Nature; Patients; Population; Predictive Value; Prevalence; Prevention; Publishing; Race; Recurrence; Reporting; Research; Resources; Risk; Risk Assessment; Sampling; Screening for cancer; South American; Specificity; Testing; Woman; base; cancer prevention; cancer risk; cohort; cost; follower of religion Jewish; high risk; high throughput technology; lifetime risk; malignant breast neoplasm; novel; population based; prototype; public health relevance

DESCRIPTION (provided by applicant): Mutations in BRCA genes are associated with 5% of all breast cancer (BC), and a larger proportion of young women with BC. Large rearrangements, not detectable by standard sequencing, account for up to 15% of deleterious BRCA mutations. The lifetime risk of developing BC associated with a BRCA mutation may be as high as 85%. We previously reported on the prevalence of deleterious BRCA mutations (31% of 110 families) in a Hispanic high-risk clinic in Los Angeles, and also identified a unique recurrent large BRCA1 rearrangement (deletion of BRCA1 exons 9-12). BRCA1 185delAG was detected in independent Hispanic families, and through haplotyping we established that they shared a common ancestral origin with Jewish carrier families. Using a new high-throughput Sequenom(R) platform, we developed a prototype multiplex panel to test for recurrent BRCA mutations, including 185delAG, and a 3-primer assay to test for the BRCA1 rearrangement mutation. We developed and piloted this 18 mutation panel in the clinical genetic cancer risk assessment setting; the panel detected 57% of deleterious mutations. Commercial confirmation of a known mutation is relatively cost-efficient. Hypotheses: 1) Using a panel of recurrent BRCA mutations found in women of Hispanic ancestry to pre-screen samples will demonstrate clinical utility and reduce genotyping cost; 2) Studying BRCA mutations from high-risk clinics serving Hispanic populations, from published literature and public databases, and from additional population-based cohorts will enable comprehensive characterization of BRCA mutations in Hispanics; 3) The characterization of the ancestral background of recurrent BRCA mutations will enhance the value of our Hispanic mutation panel. Methods: An expended panel will be created to account for up to 90% of BRCA mutations among Hispanic populations. Blood/DNA samples and clinical data from Hispanic patients will be collected from a new consortium of high-risk clinics and population-based cohorts. 628 samples from high-risk clinics will be prospectively analyzed for BRCA mutations using our revised Hispanic Mutation Panel prior to BRCA full sequencing. 909 samples from 2 high-risk clinics and 2 population-based cohorts will be analyzed for the BRCA1 large rearrangement del (ex9-12). We will use ancestral informative markers to characterize the admixture of carriers of recurrent BRCA mutations and the ancestral origin of the mutations. Haplotyping will be used to estimate the age of the del (ex 9-12) mutation. Summary: BC is the most common cancer and the leading cause of cancer death in Hispanic women. The unique BRCA panel will reduce testing cost for high-risk Hispanics, and enable more women to benefit from limited resources. Knowledge of the ancestry of recurrent mutations may make the panel more effective. Understanding the genetic etiology of BC in Hispanics will enable screening and cancer prevention. PUBLIC HEALTH RELEVANCE: Breast Cancer is the most common cancer and the leading cause of cancer death in Hispanic women. A unique Hispanic BRCA mutation test will reduce the BRCA testing cost for high-risk Hispanics, and enable more women to benefit from limited resources. This study may lead to more efficient breast cancer risk assessment for Hispanic women, which will allow them to make informed decisions to reduce the risk of advanced breast cancers.

描述（由申请人提供）：BRCA基因突变与5%的乳腺癌（BC）和更大比例的年轻女性BC相关。标准测序无法检测到的大重排占有害BRCA突变的15%。发生与BRCA突变相关的BC的终生风险可能高达85%。我们先前报道了在洛杉矶的一个西班牙裔高危诊所中有害BRCA突变的流行率（110个家庭中的31%），并且还鉴定了一种独特的复发性大BRCA 1重排（BRCA 1外显子9-12缺失）。在独立的西班牙裔家庭中检测到BRCA 1 185 delAG，通过单体型分析，我们确定他们与犹太携带者家庭有共同的祖先起源。使用一种新的高通量Sequenom（R）平台，我们开发了一种原型多重面板来测试复发性BRCA突变，包括185 delAG，以及一种3引物检测来测试BRCA 1重排突变。我们在临床遗传癌症风险评估环境中开发并试点了这18个突变面板;该面板检测到57%的有害突变。对已知突变的商业确认相对具有成本效益。假设条件：1）使用一组在西班牙裔女性中发现的复发性BRCA突变来预筛选样本将证明临床实用性并降低基因分型成本; 2）研究来自为西班牙裔人群服务的高风险诊所、来自已发表文献和公共数据库以及来自其他基于人群的队列的BRCA突变将能够全面表征西班牙裔人群中的BRCA突变; 3）复发性BRCA突变的祖先背景的表征将增强我们的西班牙裔突变面板的价值。方法：将创建一个扩展面板，以解释西班牙裔人群中高达90%的BRCA突变。来自西班牙裔患者的血液/DNA样本和临床数据将从一个新的高风险诊所和基于人群的队列中收集。在BRCA全测序之前，将使用我们修订的西班牙裔突变面板对来自高风险诊所的628份样本进行BRCA突变前瞻性分析。将分析来自2个高风险诊所和2个基于人群的队列的909份样本的BRCA 1大重排缺失（ex 9 -12）。我们将使用祖先信息标记来表征复发性BRCA突变携带者和突变的祖先起源的混合物。将使用单体型分析来估计del（ex 9-12）突变的年龄。BC是西班牙裔女性最常见的癌症，也是癌症死亡的主要原因。独特的BRCA检测试剂盒将降低高风险西班牙裔的检测成本，并使更多女性从有限的资源中受益。了解复发性突变的祖先可能会使小组更有效。了解西班牙裔BC的遗传病因将使筛查和癌症预防成为可能。 公共卫生相关性： 乳腺癌是西班牙裔妇女最常见的癌症，也是癌症死亡的主要原因。独特的西班牙裔BRCA突变检测将降低高危西班牙裔的BRCA检测成本，并使更多的妇女从有限的资源中受益。这项研究可能会为西班牙裔女性带来更有效的乳腺癌风险评估，这将使她们能够做出明智的决定，以降低晚期乳腺癌的风险。