Acquired genetic alterations in tumor cells dictate the development of high-risk neuroblastoma and clinical outcomes

Abstract

BackgroundDetermining the driving factors and molecular flow-through that define the switch from favorable to aggressive high-risk disease is critical to the betterment of neuroblastoma cure.MethodsIn this study, we examined the cytogenetic and tumorigenic physiognomies of distinct population of metastatic site- derived aggressive cells (MSDACs) from high-risk tumors, and showed the influence of acquired genetic rearrangements on poor patient outcomes.ResultsKaryotyping in SH-SY5Y and MSDACs revealed trisomy of 1q, with additional non-random chromosomal rearrangements on 1q32, 8p23, 9q34, 15q24, 22q13 (additions), and 7q32 (deletion). Array CGH analysis of individual clones of MSDACs revealed genetic alterations in chromosomes 1, 7, 8, and 22, corresponding to a gain in the copy numbers of LOC100288142, CD1C, CFHR3, FOXP2, MDFIC, RALYL, CSMD3, SAMD12-AS1, and MAL2, and a loss in ADAM5, LOC400927, APOBEC3B, RPL3, MGAT3, SLC25A17, EP300, L3MBTL2, SERHL, POLDIP3, A4GALT, and TTLL1. QPCR analysis and immunoblotting showed a definite association between DNA-copy number changes and matching transcriptional/translational expression in clones of MSDACs. Further, MSDACs exert a stem-like phenotype. Under serum-free conditions, MSDACs demonstrated profound tumorosphere formation ex vivo. Moreover, MSDACs exhibited high tumorigenic capacity in vivo and prompted aggressive metastatic disease. Tissue microarray analysis coupled with automated IHC revealed significant association of RALYL to the tumor grade in a cohort of 25 neuroblastoma patients. Clinical outcome association analysis showed a strong correlation between the expression of CFHR3, CSMD3, MDFIC, FOXP2, RALYL, POLDIP3, SLC25A17, SERHL, MGAT3, TTLL1, or LOC400927 and overall and relapse-free survival in patients with neuroblastoma.ConclusionTogether, these data highlight the ongoing acquired genetic rearrangements in undifferentiated tumor-forming neural crest cells, and suggest that these alterations could switch favorable neuroblastoma to high-risk aggressive disease, promoting poor clinical outcomes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1463-y) contains supplementary material, which is available to authorized users.

Exome sequencing of oral squamous cell carcinoma in users of Arabian snuff reveals novel candidates for driver genes

“…CSMD3 was mutated in 25% of the tumors; three of the mutations were moderately to highly damaging, of which one already described in COSMIC. The function of this gene in not fully understood, with both tumor suppressor and oncogenic properties described . Since the gene was amplified in another two samples, the identified mutations may be activating.…”

“…The function of this gene in not fully understood, with both tumor suppressor and oncogenic properties described. 29,30 Since the gene was amplified in another two samples, the identified mutations may be activating. CRB1 was mutated in four samples (20%); three of the mutations were predicted as deleterious and two have already been reported in COSMIC.…”

Diagnostic and Prognostic Implications of Ribosomal Protein Transcript Coordination in Human Cancers

“…Individual RPs have also been associated with specific tumor phenotypes. For example, RPL3 regulates chemotherapy response in certain lung and colon cancers, associates with the high-risk neuroblastoma subtype, and may have a role in the acquisition of lung cancer multidrug resistance (Khan et al 2015;Russo et al 2016;. Breast cancers with elevated expression of RPL19 are more sensitive to apoptosis mediated drugs that induce endoplasmic reticulum stress (Hong et al 2014).…”

“…Perturbations of RP expression have been found in numerous human cancers, including those of the breast, pancreas, bladder, brain and many other tissues (Lai and Xu 2007;Artero-Castro et al 2011;Jung et al 2011;Hong et al 2014;Kardos et al 2014;Khan et al 2015;Paquet et al 2015;Yong et al 2015;Russo et al 2016;Sim et al 2016;Fan et al 2017;Shi et al 2017). Mutations and deletions of RP-encoding genes have also been found in endometrial cancer, colorectal cancer, glioma, and various hematopoietic malignancies (Goudarzi and Lindstrom 2016;Ajore et al 2017;Fancello et al 2017).…”

Alternative splicing in neuroblastoma generates RNA-fusion transcripts and is associated with vulnerability to spliceosome inhibitors

“…Gain of 17q is the most frequently occurring genomic alteration in high-risk neuroblastoma and a marker for adverse clinical outcome (1), whereas 22q alterations have been reported to be involved in the transition to metastatic and more aggressive neuroblastoma (20). We analyzed the fusion transcripts occurring exclusively in low/intermediate-risk and exclusively in high-risk tumors as well as fusion transcripts common to low/intermediate-risk and high-risk levels ( Supplementary Table 4 -5).…”