Somatic mutations in specific and connected subpathways are associated with short neuroblastoma patients’ survival and indicate proteins targetable at onset of disease

Abstract

Neuroblastoma (NB) is an embryonic malignancy of the sympathetic nervous system with heterogeneous biological, morphological, genetic and clinical characteristics. Although genomic studies revealed the specific biological features of NB pathogenesis useful for new therapeutic approaches, the improvement of high-risk (HR)-NB patients overall survival remains unsatisfactory. To further clarify the biological basis of disease aggressiveness, we used whole-exome sequencing to examine the genomic landscape of HR-NB patients at stage M with short survival (SS) and long survival (LS). Only a few genes, including SMARCA4, SMO, ZNF44 and CHD2, were recurrently and specifically mutated in the SS group, confirming the low recurrence of common mutations in this tumor. A systems biology approach revealed that in the two patient groups, mutations occurred in different pathways. Mutated genes (ARHGEF11, CACNA1G, FGF4, PTPRA, PTK2, ANK3, SMO, NTNG2, VCL and NID2) regulate the MAPK pathway associated with the organization of the extracellular matrix, cell motility through PTK2 signaling and matrix metalloproteinase activity. Moreover, we detected mutations in LAMA2, PTK2, LAMA4, and MMP14 genes, impairing MET signaling, in SFI1 and CHD2 involved in centrosome maturation and chromosome remodeling, in AK7 and SPTLC2, which regulate the metabolism of nucleotides and lipoproteins, and in NALCN, SLC12A1, SLC9A9, which are involved in the transport of small molecules. Notably, connected networks of somatically mutated genes specific for SS patients were identified. The detection of mutated genes present at the onset of disease may help to address an early treatment of HR-NB patients using FDA-approved compounds targeting the deregulated pathways.

19p loss is significantly enriched in older age neuroblastoma patients and correlates with poor prognosis

“…Additionally, inactivating somatic mutations in SMARCA4 have been reported in many cancer cell lines, including non-small cell lung cancer and small cell carcinoma of the ovary 21,22 . Recently, we and others have found SMARCA4 somatic point mutations in NB, highlighting its role in the oncogenesis of this neuroblastic tumor 7,23 .…”

“…Genome-wide association studies, high-throughput sequencing and microarray gene expression-based studies have identified multiple genetic changes that characterize NB -both hereditable and somatically acquired [6][7][8][9][10][11] . Genetic alterations occurring in noncoding DNA such as TERT rearrangements 12 and point mutations in regulatory elements of transcription factor binding sites 13 also contribute to NB development.…”

An age-based, RNA expression paradigm for survival biomarker identification for pediatric neuroblastoma and acute lymphoblastic leukemia

“…A recent review regarding RND3 specifically evaluated the pro- and anti-cancer functions and concluded that indeed, the overall impact of RND3 is context dependent [28]. Mutation of SLC12A1 has been associated with a short survival in NBL [29]. POF1B has no known, previous connection to NBL and little connection to cancer in general.…”

Transcription Factors Involved in Tumorigenesis Are Over-Represented in Mutated Active DNA-Binding Sites in Neuroblastoma

“…Next-generation sequencing studies of neuroblastoma have documented low somatic mutation rates and few recurrently mutated genes. Indeed, only mutations in ALK, ATRX, and TERT have been identified as the most frequent genetic abnormalities (9)(10)(11)(12). Recent studies have shown that disease-associated genomic variation is commonly located in regulatory elements in the human population (13).…”