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Somatic mutations in specific and connected subpathways are associated with short neuroblastoma patients’ survival and indicate proteins targetable at onset of disease
Author(s) -
Esposito Maria Rosaria,
Binatti Andrea,
Pantile Marcella,
Coppe Alessandro,
Mazzocco Katia,
Longo Luca,
Capasso Mario,
Lasorsa Vito Alessandro,
Luksch Roberto,
Bortoluzzi Stefania,
Tonini Gian Paolo
Publication year - 2018
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31748
Subject(s) - biology , cancer research , genetics , mutation , gene , exome sequencing
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.