Abstract
Neuroblastoma (NB) is a childhood solid malignant tumor originating from precursor cells of the peripheral nervous system. We have previously established a risk classification system based on DNA copy number profiles. To further explore the pathogenesis of NBs in distinct risk groups, we performed whole-exome sequencing analysis of 57 primary and 7 recurrent/metastatic tumors with unique chromosomal aberration profiles as categorized by our genomic sub-grouping system. Overall, a low frequency of somatic mutations was found. Besides ALK (4/64, 6.3%), SEMA6C, SLIT1 and NRAS, genes involved in the axon guidance pathway, were identified as recurrently mutated in 6 of 64 tumors (9.4%). Pathway enrichment analysis revealed enrichment of 25 mutated genes in the mitogen-activated protein kinase (MAPK) pathway, 13 genes in the Wnt pathway, and 12 genes in the axon guidance pathway. Genomic analyses demonstrated that primary and matched recurrent or metastatic tumors obtained from sporadic and monozygotic twin NBs were clonally related with variable extents of genetic heterogeneity. Monozygotic twin NBs displayed different evolutionary trajectories. These results indicate the involvement of the axon guidance, MAPK and Wnt pathways in NB and demonstrate genomic diversity with NB progression.
Highlights
Neuroblastoma (NB) is one of the most common solid tumors in children, which originates from precursor cells of the peripheral nervous system
We have previously established a genomic subgrouping system based on array CGH analysis for the risk stratification of neuroblastoma [20, 21]
The S group was divided into Ss (s, MYCN non-amplification) and Sa (a, MYCN amplification) subgroups according to the MYCN copy number, and the P group into P1 (1p loss and 17q gain), P2 (1p loss, 11q loss and 17q gain), P3 (11q loss and 17q gain) and P4 (17q gain) subgroups, each of which was further split into s and a subsets in light of MYCN amplification status
Summary
Neuroblastoma (NB) is one of the most common solid tumors in children, which originates from precursor cells of the peripheral (sympathetic) nervous system. NB patients are stratified into low-, intermediate-, or high-risk categories based on a risk assessment of well-defined prognostic factors including the age at diagnosis, International Neuroblastoma Staging System (INSS) stage, tumor histopathology, MYCN amplification status and tumor DNA ploidy. The extreme clinical heterogeneity of NB reflects the complexity of genetic and genomic events associated with disease development and progression. MYCN oncogene amplification is present in approximately 20% of NB patients and correlates with tumor progression, advanced disease stages and poor outcome [1, 2]. Chromosomal aberrations such as 1p loss, 11q loss and 17q gain have been shown to predict poor patient outcome [1, 2]. Chromosomal deletions and sequence alterations in the ARID1A/1B genes, which regulate chromatin remodeling, have been detected in 11% of NB patients [19]
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