SP 1

Genomic characterization and modeling of tumor progression

Neuroblastome is a malignant tumor of the sympathetic nervous system and accounts for roughly 8% of cancers in childhood. A hallmark of neuroblastoma is its broad diversity in clinincal courses: In about half of the patients, the tumor and even metastases may regress spontaneously without any treatment. In the remaining patients, however, relapses and progression of the disease occurs frequently despinte intensive multimodal therapy. In most of these patients, the tumor acquires resistance to chemotherapy over time, and the children ultimately die from the disease. The molecular mechanisms of the different clinical courses of disease and treatment resistance at relapse have remained largely enigmatic to date.

In this project, we are aming to determine cancer genes Tumorigenesis is an evolutionary process driven by the continuous acquisition of somatic mutations in individual cells and subsequent selection processes. The low genetic complexity of pediatric tumors may facilitate the identification of drivers and modulators of malignant tumor evolution. In this project, we investigate genetic alterations detected in serial tumor biopsies of neuroblastoma to understand basic principles of tumor development and progression. Aided by computational analyses, we will select mutated candidate genes emerging during disease progression from genome sequencing data of primary neuroblastoma. The relevance of these genes as drivers or modulators of tumor progression will be examined in neuroblastoma model systems. We expect that our study will substantially advance our understanding of general evolutionary mechanisms underlying neoplastic transformation and chemotherapy resistance, and will provide novel entry points for developing molecularly targeted therapies for progressive neuroblastoma.