Growth, progression and chromosome instability of Neuroblastoma: a new scenario of tumorigenesis?

Tonini, Gian Paolo

doi:10.1186/s12885-016-2986-6

Cited by 26 publications

(40 citation statements)

References 42 publications

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“…Particularly relevant groups of clustered genes mutated in SS were involved in centrosome maturation, in the regulation of the cell cycle, in ciliary basal body docking ( CDK5RAP2 , CDK11A , CEP89 , TUBGCP6 and SFI1 ) and in cilium assembly (the recurrently and SS specifically mutated SMO , and GAS8 , BBS10 and AK7 ). Our observations on the mutations linked to the chromosome remodeling pathway in SS tumors support the role of chromosome instability in NB, providing further explanation for the observed CNA in patients with fatal outcomes …”

Section: Discussionsupporting

confidence: 80%

“…9 Particularly relevant groups of clustered genes mutated in SS were involved in centrosome maturation, in the regulation of the cell cycle, in ciliary basal body docking (CDK5RAP2, CDK11A, CEP89, TUBGCP6 and SFI1) and in cilium assembly (the recurrently and SS specifically mutated SMO, and GAS8, BBS10 and AK7). Our observations on the mutations linked to the chromosome remodeling pathway in SS tumors support the role of chromosome instability in NB, 45 providing further explanation for the observed CNA in patients with fatal outcomes. 4,46 The clustering of somatic mutations observed in SS patients reflected two phenomena: specific functions targeted in several SS patients, as observed for the RAF/MAPK signaling component, and co-occurrence in the same patient of mutations in two or more functionally connected genes.…”

Section: Discussionsupporting

confidence: 79%

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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

Esposito

Binatti

Pantile

et al. 2018

Intl Journal of Cancer

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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.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 79%

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

Esposito

Binatti

Pantile

et al. 2018

Intl Journal of Cancer

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“…This hypothesis is also supported by the discovery of chromothripsis, a catastrophic defect mainly occurring in chromosome 5 that damages almost all chromosome regions [41]. More recently, I suggested that chromosomal instability (CIN) plays a crucial role in the neuroblastoma development [42]. CIN is a feature of most cancers and can be caused by abnormal mitosis, failure in the microtubule and centrosome dynamics, or spindle apparatus, abnormal control of double-strand break repair, telomere maintenance, and abnormal telomere function.…”

Section: Chromosome Instability and Neuroblastomamentioning

confidence: 85%

The Origin of Neuroblastoma

Tonini¹

2017

Neuroblastoma - Current State and Recent Updates

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It is widely accepted that neuroblastoma origin from Neural Crest Cells (NCC). NCC is a group of embryonic cells located in proximity to neural tube. During the embryonic development they migrate to generate the ganglia of sympathetic nervous system and the adrenal medulla. More than 50% of neuroblastoma masses are detected in the abdomen but the phases of tumorigenesis during the embryonic life are still unknown. Neuroblastoma cells show numerous copy number aberrations (CNAs), both numerical and structural. Several non-random CNAs are detected in clinical stage 4 and associated with tumor aggressiveness. On the contrary, neuroblastoma cells of infants or young patients have several numerical CNAs that are associated with a favorable outcome. MYCN oncogene amplification was one of the first genetic abnormalities observed in neuroblastoma and was found correlated to tumor aggressiveness. About 1% of all neuroblastoma show a hereditable fashion. Nowadays, the ALK gene has been discovered as predisposition gene for neuroblastoma. Moreover, thank to the genome-wide association studies, BARD1, LMO1 and LIN28 genes have been found linked to neuroblastoma predisposition. The two-step and multistep models are not satisfied the genesis of this tumor making the study of neuroblastoma tumorigenesis mandatory. Recently, the role of chromosome instability (CIN) became prominent to explain the neuroblastoma development. Indeed, the chromothripsis was observed in neuroblastoma cells of clinical stage 4, supporting the high genomic instability of these cells. The role of CIN in neuroblastoma is still unclear, but several experimental data suggest that CIN has a pivotal part in the genesis of neuroblastoma.

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“…The most aggressive tumor in children older than 1 years of age, shows numerous copy number variations (CNVs) such as deletion, gains and gene amplification with homogenously staining region and/or double min and/or entire chromosome extra-copies ( 3 ). Two type of CNVs can occur in tumor cells: Structural CNVs that shows structural chromosome changes such as deletion, amplification and gross chromosome rearrangement, and numerical CNVs that involves gain or loss of whole chromosomes ( 4 ). Tumor aggressiveness has been observed strongly associated with such structural CNVs whereas localized tumors, belonging to patients at low- and intermediate-risk, are less aggressive and they have numerical CNVs, prevalently.…”

Section: Introductionmentioning

confidence: 99%

Chromosome instability in neuroblastoma (Review)

2018

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Neuroblastoma is a neural crest-derived tumor that accounts for 7–10% of all malignancies in children and ~15% of all childhood cancer-associated mortalities. Approximately 50% of patients are characterized as high-risk (HR) and have an overall survival of <40% at 5 years from diagnosis. HR patients with unfavorable prognosis exhibit several structural copy number variations (CNVs), whereas localized tumors belonging to patients in the low- and intermediate-risk classes, have favorable outcomes and display several numerical CNVs. Taken together these results are indicative of chromosome instability (CIN) in neuroblastoma tumor cells. The present review discusses multiple aspects of CIN including methods of measuring CIN, CIN targeting as a therapeutic strategy in cancer and the effects of CIN in neuroblastoma development and aggressiveness with particular emphasis on the CIN gene signature associated with HR neuroblastoma patients.

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Growth, progression and chromosome instability of Neuroblastoma: a new scenario of tumorigenesis?

Cited by 26 publications

References 42 publications

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

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

The Origin of Neuroblastoma

Chromosome instability in neuroblastoma (Review)

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