Neuroblastoma is a tumor arising from the nervous system and occurs almost exclusively in children. Unfortunately, about half of these tumor are very aggressive and despite very intensive treatment still difficult to cure. New techniques allow studying these tumor genomes in great detail and revealed very low rates of small genomic changes (mutations), whereas larger alterations that cause loss or gain of genomic segments occur very frequently. One particular gene, coined MYCN, discovered years ago, plays a central role in this disease and high MYCN levels typically infer a poor prognosis. Recently, the regulatory processes involved in controlling gene activity have been shown to serve as tractable drug targets. In this proposal, I will study novel candidate neuroblastoma oncogenes involved in these processes, named MAZ, BRD3 and BRG1/PHF6. In addition to their role in control of gene activity, I will also evaluate their effect on so-called replication stress, a condition arising in rapidly growing cancer cells that experience stress due to high levels of DNA replication, using cellular systems as well as animal models. Given that a particular type of folding, termed G-quadruplex (G4), plays a significant role in these pathways and also given the fact that they are druggable, I aim to scrutinize the cancer genomes for such G4 forming motifs and evaluate the therapeutic potential of the newly identified oncogenes MAZ, BRD3 and BRG1/PHF6 and G-quadruplex combination therapies.