Multi-omics approach including structural variations in the genome of medulloblastoma to detect novel targets

儿童脑瘤是儿童癌症相关死亡的主要原因。尽管在这些肿瘤的基础研究和临床治疗方面取得了长足的进步，但仍然迫切需要更有效的治疗方法，特别是对髓母细胞瘤等恶性脑肿瘤。与转录、遗传和表观遗传学相比，髓母细胞瘤在结构DNA变异(SVS)方面的基因组图景迄今还没有得到很好的描述。因此，迫切需要对髓母细胞瘤中的SVS进行全面的鉴定，并对由于这些SVS而导致肿瘤生长的分子病理机制进行表征，尤其是为了开发新的、更有效的治疗方法。因此，我们将在本项目中开展包括髓母细胞瘤长读测序在内的高度整合的多组学方法，以全面描述这些肿瘤中的SVS，并发现新的致癌驱动因素。我们将对我们的40名临床特征良好的髓母细胞瘤患者进行分子上的重新基因组组装(包括DNA甲基化、拷贝数分析、RNA测序和磷酸化蛋白质组图谱)。这些新产生的数据将以多维方法进行分析，从而提供包括这些肿瘤中的SVS在内的基因组景观的全面概述，这反过来将显著提高对髓母细胞瘤发病机制的理解，从而揭示新的治疗靶点的证据。

Pediatric brain tumors are the leading cause of cancer-related death in children. Despite considerable advances in basic research and clinical treatment of these tumors, there is still an urgent need for more effective therapies, especially for malignant brain tumors such as medulloblastoma. Compared to transcriptional, genetic and epigenetic profiles, the genomic landscape of medulloblastomas with regard to structural DNA variations (SVs) is so far less well characterized. A comprehensive identification of SVs in medulloblastomas and the characterization of molecular pathomechanisms that drive tumor growth as a result of these SVs are therefore urgently required, not the least for the development of new, more effective treatment approaches. Therefore, we will carry out a highly integrative “multi-omics” approach including long-read sequencing of medulloblastomas in this project in order to comprehensively characterize the SVs in these tumors and to discover novel oncogenic drivers. We will perform a de novo genome assembly on our molecularly (including DNA methylation, copy number analysis, RNA sequencing, and phospho-proteome profiling) and clinically well characterized cohort of 40 medulloblastoma patients. These newly generated data will be analyzed in a multidimensional approach and will thus provide a comprehensive overview of the genomic landscapes including the SVs in these tumors, which in turn will significantly improve the understanding of medulloblastoma pathogenesis and thereby reveal evidence for novel therapeutic targets.