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.

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“…RUSC2 is a less investigated multi-structural domain protein that is functionally associated with the Rap and Rab GTPase families. Mutations in RUSC2 in neuroblastoma have been identified as potential drivers ( 47 ). Duan has demonstrated that RUSC2 is commonly expressed in diverse lung cancer cells, knockdown of RUSC2 effectively inhibits the migration of lung cancer cells, and RUSC2 regulates the progression of lung cancer through epidermal growth factor receptor (EGFR) signaling ( 48 ).…”