Copy number driven dependency genes implicated in core regulatory circuits and cellular states in NB
Ponente: Frank Speleman
Center of Genetics Research / University of Ghent [Ghent, Belgium]
Host: Jesús María Hernández Rivas
Fecha: 05/10/2017 - 05/10/2017
Salón de Actos del Centro de Investigación del Cáncer
Neuroblastoma is a deadly pediatric neural crest derived tumor arising from sympathetic neuronal precursor cells. Deeper understanding of the enigmatic biology of neuroblastoma may hold the key to novel more effective and less toxic treatment. While ALK activating mutations are detected in nearly 10% of cases, other mutations affecting RAS-pathway genes, epigenetic regulators and genes implicated in neuritogenesis occur at lower frequencies thus limiting precision medicine options. In contrast to mutations, large copy number alterations (CNAs) in neuroblastoma are highly recurrent involving, amongst others, gain of chromosome 17q as the most frequent CNA in high risk MYCN amplified (MNA) and non-amplified (MNnA) tumors. Also, the finding of gains for a syntenic 17q region in MYCN driven mouse neuroblastomas further supports the hypothesis that one or more 17q genes are essential for neuroblastoma development. Non-mutated genes essential for tumor maintenance (also called dependency genes) have recently gained interest as they represent hitherto unexplored novel drug targets, thus holding the potential to expand current precision oncology drugging portfolios. We identified a total of 1078 and 814 dosage sensitive candidate dependency genes with prognostic impact in the MNA and MNnA high risk NB tumors, respectively, of which 231 (13.9%) are common in both ranked gene lists. The observation of several known genes involved in MNA neuroblastomas including MYCN on 2p, CHD5, CAMTA1 and KIF1B on 1p and BIRC5 on 17q gene supports the validity of our data-mining approach. Within the high-risk tumor cohort, BRIP1/FANCJ was marked as top ranked gene. We will present an update on in vitro and in vivo findings supporting the role of BRIP1/FANCJ dependency gene in NB through its role in control of replicative stress. BRIP1/FANCJ is part of a module of co-regulated genes implicated in cell cycle, DNA replication and repair, and G2/M control, several of which are bona fide FOXM1 target genes, including BRIP1/FANCJ itself. We propose that BRIP1/FANCJ is a key component of a broader tightly coordinated DNA damage/replicative stress response pathway protecting neuroblastoma cells from excessive levels of replicative stress thus ensuring unperturbed DNA replication and avoiding replication-transcription conflicts in these highly proliferative cancer cell. In an independent approach to prioritize 17q genes for further functional study, we identified the TBX2 transcription factor as highest ranked gene following hokey stick plot analysis for 17q genes marked by H3K27ac. TBX2 is part of the recently described core regulatory network in NB and also acts as a dependency gene. Remarkably, the TBX2 locus lies in the immediate vicinity of BRIP1, suggesting that this might represent at least one of the critical 17q segments implicated in NB formation.