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

儿童脑肿瘤是儿童癌症相关死亡的主要原因。尽管这些肿瘤的基础研究和临床治疗取得了相当大的进展，但仍然迫切需要更有效的治疗方法，特别是对于髓母细胞瘤等恶性脑肿瘤。与转录、遗传和表观遗传谱相比，髓母细胞瘤关于结构DNA变异（SVs）的基因组图谱迄今尚未得到很好的表征。因此，迫切需要全面鉴定成神经管细胞瘤中的SVs，并表征由这些SVs驱动肿瘤生长的分子病理机制，而不仅仅是开发新的、更有效的治疗方法。因此，我们将在本项目中开展高度整合的“多组学”方法，包括髓母细胞瘤的长读测序，以全面表征这些肿瘤中的SVs并发现新的致癌驱动因素。我们将对40名髓母细胞瘤患者的分子（包括DNA甲基化、拷贝数分析、RNA测序和磷酸化蛋白质组分析）和临床特征良好的队列进行从头基因组组装。这些新生成的数据将以多维的方式进行分析，从而提供包括这些肿瘤中sv在内的基因组景观的全面概述，这反过来将显著提高对成神经管细胞瘤发病机制的理解，从而为新的治疗靶点提供证据。

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.