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

描述(申请人提供)：乳腺癌(BRCA)是美国女性中最常见的确诊癌症(患病率为260万)，终身风险为八分之一，死亡率约为40,000/年。大约10%的BRCA聚集性在家庭中(26万美国妇女)；然而，75%的遗传因素是未知的。“遗传缺失”被认为在一定程度上是由于罕见的遗传易感变异。我们使用独特的全州家谱和癌症数据库进行的观察与此一致。大的高危家系被接受为稀有的风险变异的丰富和相关的研究设计来追踪它们。罕见风险变异的发现很重要，因为它们可能与携带这些变异的妇女直接相关。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已识别的基因中。因此，新的罕见风险的识别 变种有可能提供直接的临床影响，以及对人群水平的易感性的洞察和该领域的新方向。两大障碍阻碍了 罕见的风险变量发现：缺乏强大的统计方法来识别大型家系 重要的基因组区域；以及遗传异质性--这两个问题对常见疾病特别具有挑战性，例如BRCA。最近，我们介绍了共享基因组片段(SGS)方法，通过模拟和原理验证的例子表明，这种方法在高危家系中识别含有罕见危险变异的染色体区域具有很好的能力。区域指导的战略允许高效、有重点的测序和分析工作，以及基于共享的强大过滤。然而，如果无法识别令人信服的区域，整个外显子组测序是一种补充策略。无论是地区性的还是整个外显子组，重要的是在一个家系中测序的病例具有潜在的易感变异/S。高危家系的成员身份肯定会增加同质性的可能性；然而，预计还会存在其他异质性来源。我们假设，分子肿瘤亚型将是识别更多基因同质性BRCA的关键。众所周知，乳腺肿瘤在细胞和分子组成上是异质性的，这种分子异质性可以归结为四种主要的肿瘤亚型，这些亚型具有相似的基因表达谱，基于“固有的”基因集。我们将研究25个具有BRCA内在特征的高危家系，以确定罕见的BRCA风险变异，并对3个随访队列(3500人)进行追踪，以识别低风险变异。我们的大规模并行测序工作将 遵循双管齐下的方法，包括区域指导和基于引人注目的共同区域的存在的整个外显子组测序。我们在独立队列中的后续研究对于证实和建立对新的BRCA易感基因如何更普遍地影响风险的更广泛的理解是必要的。总而言之，我们相信我们的研究策略是有充分基础的，高度创新的，是识别新的BRCA易感变异的强有力的方法。

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.