Hereditary Breast Cancer and Novel Hispanic BRCA Mutations

描述(申请人提供)：BRCA基因突变与5%的乳腺癌(BC)相关，并与患BC的年轻女性的更大比例有关。标准测序无法检测到的大范围重排导致了高达15%的有害BRCA突变。与BRCA突变相关的罹患BC的终生风险可能高达85%。我们之前在洛杉矶的一个西班牙裔高危诊所中报道了有害的BRCA突变的流行(110个家庭中有31%)，还发现了一种独特的反复发生的大BRCA1重排(BRCA1外显子9-12的缺失)。在独立的西班牙裔家庭中检测到BRCA1185delAG，通过单倍体分析，我们确定他们与犹太携带者家族有共同的祖先起源。使用新的高通量Sequenom(R)平台，我们开发了一个原型多路复用板来检测包括185delAG在内的BRCA复发突变，并开发了一个3引物法来检测BRCA1重排突变。我们在临床遗传癌风险评估环境中开发并试点了这一18个突变小组；该小组检测到57%的有害突变。已知突变的商业确认相对来说成本效益更高。假设：1)使用在西班牙裔女性祖先中发现的一组反复出现的BRCA突变来预先筛选样本，将证明临床实用，并降低基因分型成本；2)从服务于西班牙裔人群的高危诊所、从已发表的文献和公共数据库以及从更多的基于人群的队列中研究BRCA突变，将使我们能够全面描述西班牙裔的BRCA突变；3)对反复发生的BRCA突变的祖先背景的表征将提高我们的拉美裔突变小组的价值。方法：将建立一个扩大的小组，以解释西班牙裔人群中高达90%的BRCA突变。西班牙裔患者的血液/DNA样本和临床数据将从一个新的高危诊所和基于人群的队列中收集。来自高危诊所的628个样本将在BRCA全序列测定之前，使用我们修订的西班牙裔突变小组进行前瞻性分析，以确定BRCA突变。将对来自2个高危诊所和2个基于人群的队列的909个样本进行BRCA1大重排Del(ex9-12)分析。我们将使用祖先信息标记来描述反复发生的BRCA突变的携带者和突变的祖先来源的混合物。单倍型将被用来估计del(ex9-12)突变的年龄。摘要：卑诗省是最常见的癌症，也是西班牙裔女性癌症死亡的主要原因。独特的BRCA小组将降低高危拉美裔美国人的检测成本，并使更多女性受益于有限的资源。了解反复发生的突变的祖先可能会使该小组更有效。了解西班牙裔BC的遗传病因将有助于筛查和癌症预防。 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。一种独特的拉美裔BRCA突变检测将降低高危拉美裔的BRCA检测成本，并使更多女性受益于有限的资源。这项研究可能会导致对西班牙裔女性进行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。

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.