In search for the lacking driver genes of neuroblastoma


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Rogier Versteeg1
1Netherlands Bioinformatics Centre

Abstract

Like many other childhood tumors, neuroblastoma have a low mutation load and only few recurrently mutated oncogenes and tumor suppressor genes. In contrast, gains and losses of chromosome arms are frequent and show consistent patterns, suggesting a prominent role in oncogenesis. The gained and lost regions are large and include hundreds of genes. We have therefore postulated that gains and losses of many genes in such regions together cause an imbalance in expression that activates cancer driving pathways. However, such a hypothesis is hard to test. We follow two approaches to elucidate the role of genomic gains and losses. Firstly, we pinpoint regions of imbalances by whole genome sequencing of large neuroblastoma series. Secondly, we identify key genes with a potential role in lineage differentiation and oncogenesis in neuroblastoma. We observed that neuroblastoma tumors include two types of tumor cells. They share the same genetic defects, but have highly divergent phenotypes. The two tumor cell types seem to correspond to two stages of normal differentiation of the adrenergic lineage. We identified the master regulators of this differentiation program. Combining these functional studies with the genomic imbalances prioritizes candidate genes that may represent the lacking driver genes of neuroblastoma.

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