High Genomic Instability Predicts Survival in Metastatic High-Risk Neuroblastoma

Stigliani, Sara; Coco, Simona; Moretti, Stefano; Oberthuer, André; Fischer, M; Theißen, Jessica; Gallo, Fabio; Garavent, Alberto; Berthold, Frank; Bonassi, Stefano; Tonini, Gian Paolo; Scaruffi, Paola

doi:10.1593/neo.121114

Cited by 45 publications

(53 citation statements)

References 48 publications

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“…1A). Similarly, genomeand transcriptome-wide analysis of high-risk neuroblastomas showed correlation between deregulation of Rho GTPase signaling and high-risk neuroblastoma independent of MYCN gene amplification status (25). We therefore investigated the effects of inhibiting the activity of ROCK molecules in neuroblastoma using specific small-molecule inhibitors of ROCK or RNAimediated gene silencing.…”

Section: Discussionmentioning

confidence: 99%

Rho-associated kinase is a therapeutic target in neuroblastoma

Dyberg

Fransson

Andonova

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Neuroblastoma is a peripheral neural system tumor that originates from the neural crest and is the most common and deadly tumor of infancy. Here we show that neuroblastoma harbors frequent mutations of genes controlling the Rac/Rho signaling cascade important for proper migration and differentiation of neural crest cells during neuritogenesis. RhoA is activated in tumors from neuroblastoma patients, and elevated expression of Rho-associated kinase (ROCK)2 is associated with poor patient survival. Pharmacological or genetic inhibition of ROCK1 and 2, key molecules in Rho signaling, resulted in neuroblastoma cell differentiation and inhibition of neuroblastoma cell growth, migration, and invasion. Molecularly, ROCK inhibition induced glycogen synthase kinase 3β-dependent phosphorylation and degradation of MYCN protein. Small-molecule inhibition of ROCK suppressed MYCN-driven neuroblastoma growth in TH-MYCN homozygous transgenic mice and MYCN gene-amplified neuroblastoma xenograft growth in nude mice. Interference with Rho/Rac signaling might offer therapeutic perspectives for high-risk neuroblastoma.N euroblastoma is a childhood tumor of the peripheral sympathetic nervous system, causing 6% of all childhood cancers but 9% of deaths from malignant tumors in children (1, 2). Approximately half of patients present with high-risk disease characterized by unresectable primary lesions and multiple metastases (2, 3). Although survival in this group has improved, the majority of the tumors show resistance to therapy with poor patient survival despite intensive multimodal therapy, necessitating the search for new therapeutic options (2).Compared with adult tumors, pediatric cancers exhibit significantly fewer genomic aberrations and mutations. In neuroblastoma, somatically acquired amplification of MYCN, hemizygous deletions of 1p and 11q, and gain of 17q are the most common chromosomal aberrations associated with a poor prognosis (3). Exome-and whole-genome sequencing analysis of neuroblastoma has reported an overall low somatic mutation count (12 to 18, median 15), with ALK being the most frequently mutated gene (7 to 10%) (4-6). In addition, chromothripsis, PHOX2B, and ATRX mutations have also been detected in a subset of highrisk tumors (4,5).Neuritogenesis is initiated during embryogenesis by a transient population of cells called the neural crest. During embryonic development, neural crest cells migrate throughout the embryo and eventually differentiate into multiple cell types, such as neurons and glial cells of the peripheral nervous system, pigment cells, fibroblasts, smooth muscle cells, and odontoblasts. The failure of neural crest cells to differentiate can result in development of cancers such as neuroblastoma and melanoma (7). A combination of Wingless (Wnt), bone morphogenetic protein, and fibroblast growth factor (FGF) signals is required to induce the formation of the neural crest and to initiate migration of neural crest cells by acquiring cell motility through epithelialmesenchymal transition (8). The no...

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Section: Discussionmentioning

confidence: 99%

Rho-associated kinase is a therapeutic target in neuroblastoma

Dyberg

Fransson

Andonova

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Indeed, detailed comparison of chromosome 1p status with expression levels showed that around 15% of the genes targeted by the deletion had a decreased expression, indicating that chromosome 1p deletion results in a gene dosage effect on a subset of genes that may be crucial for NB development . Further detailed analyses have shown that SCAs may lead to an alteration of gene expression affecting loss of cell‐cycle control and deregulation of Rho guanosine triphosphates functioning in neuritogenesis . Although copy‐number alterations are a hallmark of NB, copy neutral loss of heterozygosity appears to be uncommon in NB tumors, but more frequent in NB cell lines …”

Section: Somatic Genetic Alterations In Nb Determined By Genomic Dna mentioning

confidence: 99%

Recent insights into the biology of neuroblastoma

Schleiermacher

Janoueix‐Lerosey

Delattre

2014

Intl Journal of Cancer

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Neuroblastoma (NB) is an embryonal tumor of the sympathetic nervous system which accounts for 8-10% of pediatric cancers. It is characterized by a broad spectrum of clinical behaviors from spontaneous regression to fatal outcome despite aggressive therapies. Considerable progress has been made recently in the germline and somatic genetic characterization of patients and tumors. Indeed, predisposition genes that account for a significant proportion of familial and syndromic cases have been identified and genome-wide association studies have retrieved a number of susceptibility loci. In addition, genomewide sequencing, copy-number and expression studies have been conducted on tumors and have detected important gene modifications, profiles and signatures that have strong implications for the therapeutic stratification of patients. The identification of major players in NB oncogenesis, including MYCN, ALK, PHOX2B and LIN28B, has enabled the development of new animal models. Our review focuses on these recent advances, on the insights they provide on the mechanisms involved in NB development and their applications for the clinical management of patients.Neuroblastoma (NB) is the most common extracranial cancer of early childhood, with an estimated incidence of 1/8,000-10,000 births.1 In France, this cancer is diagnosed in 130-150 new patients every year, and accounts for approximately 15% of cancer-related deaths.2 Median age at diagnosis is 18 months, 40% of cases being diagnosed before 1 year of age. NB arises from embryonic cells that form the primitive neural crest, originating either in the adrenal medulla or in the paraspinal ganglia of the sympathetic nervous system. In case of metastases, these are most frequently observed in bone marrow, bone, lymph nodes, liver or subcutaneous tissue, other metastatic localizations occurring much rarer.The hallmark of NB is its wide range of clinical courses, with, on the one hand, a possibility of cellular maturation or spontaneous regression even in case of metastatic disease, or on the other hand, life-threatening tumor progression despite all treatment. Thus, prognostic factors have been sought for to identify risk groups and to stratify treatment approaches. The clinical parameters age and stage have been used, together with pathological features, to define different risk groups at the time of diagnosis.3 Children diagnosed with a NB before the age of 18 months have a better outcome than those diagnosed at a later age. 4 Patients with localized disease (INRG staging system L1 and L2; localized disease without or with image-defined risk factors precluding surgical resection) have a better prognosis than those with metastatic disease (INRG stage M), whose outcome remains dismal especially in older children. To date, different recurrent genetic markers have also been included in risk stratification schemes. It is likely that with the increase of knowledge about the underlying genetic features of NB, additional genetic information will be included for the definition of pro...

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“…In patients with myelodysplasia, a complex karyotype has been related to poor prognosis [159] and the multifactor copy number index has shown to be an unfavorable prognostic factor in patients with Ewing sarcoma [161]. In a similar manner, patients with high-risk neuroblastomas and only few copy number aberrations had a better prognosis [160].…”

Section: Expert Commentarymentioning

confidence: 99%

Fractal dimension of chromatin: potential molecular diagnostic applications for cancer prognosis

Metze

2013

Expert Review of Molecular Diagnostics

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Fractal characteristics of chromatin, revealed by light or electron microscopy, have been reported during the last 20 years. Fractal features can easily be estimated in digitalized microscopic images and are helpful for diagnosis and prognosis of neoplasias. During carcinogenesis and tumor progression, an increase of the fractal dimension (FD) of stained nuclei has been shown in intraepithelial lesions of the uterine cervix and the anus, oral squamous cell carcinomas or adenocarcinomas of the pancreas. Furthermore, an increased FD of chromatin is an unfavorable prognostic factor in squamous cell carcinomas of the oral cavity and the larynx, melanomas and multiple myelomas. High goodness-of-fit of the regression line of the FD is a favorable prognostic factor in acute leukemias and multiple myelomas. The nucleus has fractal and power-law organization in several different levels, which might in part be interrelated. Some possible relations between modifications of the chromatin organization during carcinogenesis and tumor progression and an increase of the FD of stained chromatin are suggested. Furthermore, increased complexity of the chromatin structure, loss of heterochromatin and a less-perfect self-organization of the nucleus in aggressive neoplasias are discussed.

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High Genomic Instability Predicts Survival in Metastatic High-Risk Neuroblastoma

Cited by 45 publications

References 48 publications

Rho-associated kinase is a therapeutic target in neuroblastoma

Rho-associated kinase is a therapeutic target in neuroblastoma

Recent insights into the biology of neuroblastoma

Fractal dimension of chromatin: potential molecular diagnostic applications for cancer prognosis

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