Neuroblastoma (NB) is an aggressive neural crest derived childhood tumor with poor survival rates, especially in

older children. Thus far, three bona fide oncogenic driver genes have been identified in neuroblastoma: MYCN,

amplified in roughly half of all aggressive neuroblastoma cases, ALK mutations or amplifications in 10% of cases

and rare LlN28B amplifications. Chromosome 17q gain is by far the most common DNA copy number alteration

in NB but thus far the causal 17q driver genes remain to be identified due to the large size of the recurrently

involved chromosome segments. In this project, we took advantage of an in silico integrative approach to identify

new driver genes located on 17q. In a first step, we used the firmly established TH-MYCN neuroblastoma mouse

model to explore the early transcriptional changes in MYCN-driven tumor development. In a second step, we

applied the CONEXIC algorithm which integrates copy number variations, gene expression data and miRNA

data, on 221 NB primary patient samples. As such, we were able to identify two new driver genes on 17q with

great therapeutic potential, namely BRIP1 and BIRCS.

For BIRCS a zebrafish model was established and subsequently crossed with the well established dl3h-MYCN

zebrafish model. In this model acceleration of NB tumor development was observed, clearly pinpointing to a

cooperative role between BIRCS and MYCN in NB development. Further evaluation of the role of BIRCS in

neuroblastoma development will be investigated using the BIRCS zebrafish model as well as exploration of

BIRCS inhibitors.

While BIRCS is involved in apoptosis as firmly established hallmark of cancer, BRIP1 represent a completely

new type of target in cancer connected to upregulated DNA damage response, a novel counter intuitive cancer

hallmark. Extensive in vitro data have been performed in our laboratory and support an oncogenic role for BRIP1

in NB. Furthermore, in keeping with the role of BRIP1 in DNA damage response, elevated protein levels of

yH2AX and RPA32 were observed upon knock down of BRIP1 .

The support of the VLK finalizing grant will allow me to perform the final and crucial experiments for the BIRCS

and BRIP1 projects and write up two additional papers for my PhD thesis. The specific goals that I aim to

achieve are: 1) finish crucial and final experiments with regard to the role of BIRCS in NB development using the

available dl3h-BIRCS zebrafish; 2) expand BRIP1 in vivo data in relation to its presumed cooperative oncogenic

function and 3) finalization of my PhD thesis. Given the research experience I gained during this PhD thesis, the

already performed experiments and my research stay at Tom Looks lab (Dana Farber Cancer Institute and

Harvard Medical School, Boston, USA) where I initiated the BIRCS project and given the excellent expertise of

the host lab, I am confident that the proposed goals will be achieved within the period of one year.