Discover and Analyze Germline-Somatic Interactions in Cancer

项目摘要 癌症是一组具有不同临床特征和分子谱的异质性疾病。 几十年的研究已经发现了许多生殖系遗传风险变异，赋予遗传性癌症 易感性和促进体细胞恶性转化的体细胞驱动突变。因为 体细胞突变出现在个体种系基因组、预先存在的种系变体的背景下 可能会影响哪些协同体细胞突变是驱动肿瘤发生所必需的。因此，这两个群体 变异体及其相互作用共同影响肿瘤的临床表型，如组织学亚型， 转移部位和对治疗的反应。然而，由于目前的研究主要是检查生殖细胞和体细胞， 虽然我们的研究对象是独立的变异体，但我们对种系-体细胞相互作用（GxS）的了解非常有限。 为了解决这一知识缺口，并促进精确肿瘤学，我们提出了一种新的计算 框架，在种系和索马（VIGAS）中相互作用的变体，共同评估这些变体的功能影响。 两组变量。使用多发性骨髓瘤（MM）作为疾病平台，我们将开发一套 生物信息学方法通过多组学数据的综合分析来发现和表征GxS。我们将 检查编码区和非编码区的各种类型的遗传变异。与现有方法不同， 基于种系和体细胞变异共同出现的简单指标，VIGAS方法旨在发现 具有生物学意义的GXS。 我们将追求四个具体目标。目标1：我们将开发一种基于VIGAS-e的方法来发现GxS， 进化选择，其中种系变体修改体细胞突变基因的选择优势。 目的二：我们将建立一种基于转录调控的VIGAS-t方法来发现GxS， 突变加剧了由种系变异体引起的预先存在的转录畸变。目标3：我们将联合收割机 VIGAS-e和VIGAS-t结果用于鉴定GxS，这些GxS聚集在共同基因和途径上，并与 与MM的临床病理特征。我们将进行实验验证顶部GxS。目标4：我们将 将VIGAS应用于各种癌症类型。跨癌症类型的比较将揭示GxS与 组织特异性，以及在不同器官中发生癌症的风险。我们将实施VIGAS， 开源跨平台工具，在在线数据库中发布GxS的全面注释， 在GitHub上创建一个用户社区。 VIGAS方法和表征的GxS将极大地提高我们对复杂的理解 肿瘤发生中的基因型-表型关系。我们的研究将揭示癌症的异质性， 生殖系基因组，并为针对个体患者的精确癌症管理奠定基础。这 将使癌症管理从被动的方法转变为更主动的方法。

PROJECT SUMMARY Cancer is a group of heterogeneous diseases with diverse clinical characteristics and molecular profiles. Decades of research have discovered many germline genetic risk variants that confer hereditary cancer susceptibilities, and somatic driver mutations that promote malignant transformations of body cells. Because somatic mutations arise in the background of an individual’s germline genome, pre-existing germline variants may influence which synergistic somatic mutations are needed to drive tumorigenesis. Thus, these two groups of variants and their interactions together affect a tumor’s clinical phenotype, such as histological subtype, metastasis sites, and response to treatments. However, as current studies mostly examine germline and somatic variants independently, our knowledge of germline-somatic interplays (GxS) is very limited. To address this knowledge gap and to facilitate precision oncology, we propose a novel computational framework, Variants Interacting in Germline and Soma (VIGAS) that jointly assess the functional impact of these two groups of variants. Using multiple myeloma (MM) as the disease platform, we will develop a suite of bioinformatics methods to discover and characterize GxS via integrative analysis of multi-omics data. We will examine various types of genetic variants in coding and noncoding regions. Unlike existing methods that use simple metrics based on co-occurrences of germline and somatic variants, the VIGAS methods aim to discover GxS with biological significance. We will pursue four specific aims. Aim 1: we will develop a VIGAS-e method to discover GxS based on evolutionary selection, in which germline variants modify selective advantages of somatically mutated genes. Aim 2: we will develop a VIGAS-t method to discover GxS based on transcriptional regulation, in which somatic mutations aggravate pre-existing transcriptional aberrations caused by germline variants. Aim 3: we will combine VIGAS-e and VIGAS-t results to identify GxS that converge on common genes and pathways and are associated with clinicopathological features of MM. We will perform experimental validations of top GxS. Aim 4: we will apply VIGAS to various cancer types. Comparisons across cancer types will reveal associations of GxS with tissue specificity, as well as the risk of developing cancers in different organs. We will implement VIGAS as open-source cross-platform tools, release comprehensive annotations of GxS in an online database, and organize a user community on GitHub. The VIGAS methods and the characterized GxS will greatly improve our understanding of the complex genotype-phenotype relationships in tumorigenesis. Our study will reveal cancer heterogeneities rooted in germline genomes and build the foundation for precision cancer management tailored to individual patients. This will transform cancer management from reactionary approaches toward more proactive approaches.