Shared Genomic Segment Analysis and Tumor Subtyping in High-Risk BrCa Pedigrees

描述（由申请人提供）：乳腺癌（BrCa）是美国女性中最常诊断的癌症（患病率为260万），其终生风险为1/8，死亡率约为40，000/年。大约10%的BrCa在家庭中聚集（260，000名美国妇女）;然而，>75%的遗传因素是未知的。“缺失的遗传性”被认为部分是由于罕见的遗传易感性变异。我们使用一个独特的全州家谱和癌症数据库的观察结果与此一致。大的高风险家系被认为是丰富的罕见风险变异和相关的研究设计，以追求他们。发现罕见的风险变异很重要，因为它们可能与携带它们的女性直接相关。此外，我们假设，更常见的，低风险和中等风险的变异也将存在于所确定的基因中。因此，识别新的罕见风险 变异有可能提供直接的临床影响，以及深入了解人群水平的易感性和该领域的新方向。两大障碍阻碍 罕见的风险变异发现：缺乏强大的统计方法来识别大型谱系 基因组区域的重要性;和遗传异质性-这两个都是特别具有挑战性的常见疾病，如溴钙。最近，我们引入了共享基因组片段（SGS）方法，通过模拟和原理验证的例子，这些方法已经被证明具有很好的能力来识别高风险家系中携带罕见风险变体的染色体区域。区域指导的策略允许高效、集中的测序和分析工作以及基于共享的强大过滤。然而，如果不能确定引人注目的区域，则全外显子组测序是一种补充策略。无论是区域还是整个外显子组，重要的是在谱系中测序的病例共享潜在的易感性变体。高风险谱系的成员资格当然增加了同质性的可能性;然而，预计将存在其他异质性来源。我们推测，分子肿瘤亚型将是至关重要的，以确定更多的遗传同质的BrCa。已知乳腺肿瘤在细胞和分子组成上是异质性的，并且这种分子异质性可以减少到基于“内在”基因集具有相似基因表达谱的四种主要肿瘤亚型。我们将研究25个高风险内在特征的BrCa家系，以确定罕见的BrCa风险变异和3个随访队列（3,500人），以确定低风险变异。我们的平行测序工作 遵循双管齐下的方法，包括区域指导和基于存在令人信服的共享区域的全外显子组测序。我们在独立队列中的随访对于确证和建立对新型BrCa易感基因如何更普遍地影响风险的更广泛理解是必要的。总之，我们相信我们的研究策略是有充分依据的，高度创新的，是鉴定新的BrCa易感性变体的有力方法。 公共卫生相关性：研究大型高危乳腺癌家系的能力，以及我们结合新的分析技术和肿瘤亚型，使我们能够识别罕见的遗传性BrCa易感性变体。这种变异的发现可能会导致识别额外的常见，低风险和中等风险的遗传因素，并改善高风险家庭和一般人群的筛查程序。

DESCRIPTION (provided by applicant): Breast cancer (BrCa) is the most frequently diagnosed cancer in women in the US (prevalence 2.6 million), poses a lifetime risk of 1 in 8, and has a death rate of ~40,000/year. About 10% of BrCa clusters in families (260,000 US women); however, >75% of heritable factors are unknown. The 'missing heritability' is thought to be, in part, due to rare inherited susceptibility variants. Our observations using a unique statewide genealogical and cancer database are consistent with this. Large high-risk pedigrees are accepted to be enriched for rare risk variants and a relevant study design to pursue them. The discovery of rare risk variants is important because they may have immediate relevance for the women carrying them. Furthermore, we hypothesize that more common, low- and moderate-risk variants will also exist in the genes identified. Hence, the identification of novel rare risk variants has the potential to provide immediate clinical impact as well as insight into susceptibility at the population-level and new directions for the field. Two major obstacles hinder rare risk variant discovery: a lack of powerful statistical methods for large pedigrees to identify genomic regions of importance; and genetic heterogeneity -both of which are especially challenging for common diseases, such as BrCa. Recently, we introduced shared genomic segment (SGS) methods which have been shown through simulation and proof-of-principle examples to have good power to identify chromosomal regions harboring rare risk variants in high-risk pedigrees. A regionally-guided strategy allows for efficient, focused sequencing and analysis efforts and strong filtering based on sharing. If, however, compelling regions cannot be identified, whole exome sequencing is a complementary strategy. Whether regional or whole exome, it is important that the cases sequenced in a pedigree share the underlying susceptibility variant/s. Membership in a high-risk pedigree certainly increases the likelihood for homogeneity; however, it is expected that other sources of heterogeneity will exist. We hypothesize that molecular tumor subtyping will be critical to identify more genetically homogeneous BrCa. Breast tumors are known to be heterogeneous in cellular and molecular make-up, and that this molecular heterogeneity can be reduced to four major tumor subtypes that have similar gene expression profiles based on 'intrinsic' gene sets. We will study 25 high-risk intrinsic-characterized BrCa pedigrees to identify rare BrCa risk variants and three follow-up cohorts (3,500 individuals) to identify lower-risk variants. Our massively-parallel sequencing efforts will follow a two-pronged approach, including regionally- guided and whole exome sequencing based on the existence of compelling shared regions. Our follow-up in independent cohorts is imperative for corroboration and to establish a broader understanding of how novel BrCa susceptibility genes more generally influence risk. In summary, we believe our research strategy is well- grounded, highly innovative and a powerful approach to identify new BrCa susceptibility variants. PUBLIC HEALTH RELEVANCE: The ability to study large high-risk breast cancer pedigrees, in addition to our incorporation of novel analysis techniques and tumor subtyping, uniquely positions us to identify rare inherited BrCa susceptibility variants. The discovery of such variant could lead to the identification of additional common, low- and moderate-risk genetic factors and improved screening procedures in high-risk families and in the general population.