RNA-Sequencing Combined With Genome-Wide Allele-Specific Expression Patterning Identifies ZNF44 Variants as a Potential New Driver Gene for Pediatric Neuroblastoma

Abstract

Introduction Neuroblastoma (NB) is one of the children’s most common solid tumors, accounting for approximately 8% of pediatric malignancies and 15% of childhood cancer deaths. Somatic mutations in several genes, such as ALK , have been associated with NB progression and can facilitate the discovery of novel therapeutic strategies. However, the differential expression of mutated and wild-type alleles on the transcriptome level is poorly studied. Methods This study analyzed 219 whole-exome sequencing datasets with somatic mutations detected by MuTect from paired normal and tumor samples. Results We prioritized mutations in 8 candidate genes ( RIMS4 , RUSC2 , ALK , MYCN , PTPN11 , ALOX12B , ZNF44 , and CNGB1 ) as potential driver mutations. We further confirmed the presence of allele-specific expression of the somatic mutations in NB with integrated analysis of 127 RNA-seq samples (of which 85 also had DNA-seq data available), including MYCN , ALK , and PTPN11 . The allele-specific expression of mutations suggests that the same somatic mutation may have different effects on the clinical outcomes of tumors. Conclusion Our study suggests 2 novel variants of ZNF44 as a novel candidate driver gene for NB.