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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. What's new? Most patients with metastatic neuroblastoma don't survive 5 years from diagnosis, despite responding well to first‐line treatments. Previous work comparing short‐survival and long‐survival patients identified some key chromosomal differences. These authors take the search deeper, conducting whole‐exome sequencing to compare somatic mutations between patients who survived at least 5 years and those who did not. They determined that mutations among the short‐survival group affected different pathways than those afflicting the long‐survival patients. In some cases, drugs already exist that target these proteins, suggesting that testing for these mutations at the time of diagnosis could indicate specific treatments. [ABSTRACT FROM AUTHOR]

Chromosome instability has a pivotal role among the hallmarks of cancer, but its transcriptional counterpart is rarely considered a relevant factor in cell destabilization. To examine transcription instability ( TIN), we first devised a metric we named TIN index and used it to evaluate TIN on a dataset containing more than 500 neuroblastoma samples. We found that metastatic tumors from high-risk ( HR) patients are characterized by significantly different TIN index values compared to low/intermediate-risk patients. Our results indicate that the TIN index is a good predictor of neuroblastoma patient's outcome, and a related TIN index gene signature ( TIN-signature) is also able to predict the neuroblastoma patient's outcome with high confidence. Interestingly, we find that TIN-signature genes have a strong positional association with superenhancers in neuroblastoma tumors. Finally, we show that TIN is linked to chromatin structural domains and interferes with their integrity in HR neuroblastoma patients. This novel approach to gene expression analysis broadens the perspective of genome instability investigations to include functional aspects. [ABSTRACT FROM AUTHOR]

The prognosis of children with metastatic neuroblastoma (NB) > 18 months at diagnosis is dismal. Since the immune status of the tumor microenvironment could play a role in the history of disease, we evaluated the expression of CD45, CD14, ARG1, CD163, CD4, FOXP3, Perforin-1 (PRF1), Granzyme B (GRMB), and IL-10 mRNAs in primary tumors at diagnosis from children with metastatic NB and tested whether the transcript levels are significantly associated to event-free and overall survival (EFS and OS, resp.). Children with high expression of CD14, ARG1 and FOXP3 mRNA in their primary tumors had significantly better EFS. Elevated expression of CD14, and FOXP3 mRNA was significantly associated to better OS. CD14 mRNA expression levels significantly correlated to all markers, with the exception of CD4. Strong positive correlations were found between PRF1 and CD163, as well as between PFR1 and FOXP3. It is worth noting that the combination of high levels of CD14, FOXP3, and ARG1 mRNAs identified a small group of patients with excellent EFS and OS, whereas low levels of CD14 were sufficient to identify patients with dismal survival. Thus, the immune status of the primary tumors of high-risk NB patients may influence the natural history of this pediatric cancer. [ABSTRACT FROM AUTHOR]

About 50% of children with neuroblastoma (NB) show a metastatic disease and have a poor prognosis. However, disease progression is greatly variable and depends on patients' age and MYCN oncogene amplification. To investigate the role of patients' age in tumor aggressiveness, we performed array-CGH and gene expression profiles of three groups (G) of metastatic NBs: G1, stage 4S patients and MYCN single copy ( MYCN−) tumors; G2, stage 4 patients, ≤18 months of age, MYCN− tumors and favorable outcome and G3, Stage 4 patients, ≥19 months with unfavorable outcome. G1 was characterized by numerical aberrations prevalently; on the contrary, all G3 tumors had structural rearrangements, whereas G2 showed an intermediate pattern. The average of numerical alterations decreased significantly from G1 to G2 to G3 ( p < 0.01). Contrarily, the number of structural aberrations increased from G1 to G2 to G3 ( p < 2.35 E−05). Noteworthy, G3/ MYCN− NBs were characterized by several complex intrachromosome rearrangements. Expression analysis of the three groups showed significant differences in genes of Rho and Ras signaling pathways, development and adhesion, cell cycle regulation and telomerase activity. Accumulation of structural alterations increased with patients' age and was associated with a more aggressive disease. Abnormal expression of genes involved in cell cycle and telomerase in G3 may be responsible for the genomic instability in this cohort of patients. The higher DNA instability observed in G3/ MYCN− NBs than in MYCN-amplified G3 may also explain why patients ≥19 months have a poor outcome independently by MYCN status. [ABSTRACT FROM AUTHOR]

Abstract: Dicer is a ribonuclease playing a key role in the biogenesis of microRNAs and small interfering RNAs. Here we report the identification of a novel splice variant of human dicer gene, the first one bearing a modified coding sequence. It encodes a truncated protein, t-Dicer that lacks the dsRNA-binding domain and is defective in one of the two RNase III catalytic centers. The splice variant was found in neuroblastoma cells and in cells induced to neuronal differentiation, whereas it was not detectable in other cell lines or in normal tissues. Interestingly, it occurred in primary neuroblastic tumors, mainly in stroma poor neuroblastomas. [ABSTRACT FROM AUTHOR]

The article presents a study to identify low intratumoral gene expression heterogeneity in neuroblastic tumors (NTs). It relates that gene expression data were analyzed by the Significance Analysis of Microarrays (SAM) and Game Theory (GT) methods. Accordingly, it shows that stroma-poor NTs (NTs-SP) and stroma-rich NTs (NTs-SR) gene signatures differ for a set of genes involved in distinct pathways, and low intratumoral heterogeneity at the messenger RNA (mRNA) level in both NT-SP and NT-SR.

Individual response to oxidative stress, due to exposure to asbestos fibres plays a significant role in the malignant pleural mesothelioma (MPM) etiology. The differential impact on MPM risk of polymorphic alleles of glutathione- S-transferases ( GSTs) and manganese superoxide dismutase ( MnSOD/SOD2) genes involved in the defence against oxidative damage has been investigated. Ninety cases of MPM and 395 controls were genotyped using the arrayed-primer extension technique. Logistic regression analysis was applied to assess the predictive role of single nucleotide polymorphisms (SNPs) potentially involved in MPM carcinogenesis after adjustment for potential confounders. An increased risk of MPM was found in subjects bearing a GSTM1 null allele (OR = 1.69, 95% CI = 1.04-2.74; p = 0.034), and in those with the Ala/Ala genotypes at codon 16 within MnSOD (OR = 3.07, 95% CI = 1.55-6.05; p = 0.001). A stronger effect of MnSOD was observed among patients without a clear exposure to asbestos fibres. No effect was found for GSTA2, GSTA4, GSTM3, GSTP1 and GSTT1 genes. These findings, if replicated, contribute substantial evidence to the hypothesis that oxidative stress and cellular antireactive oxygen species systems are involved in the pathogenesis and in the natural history of MPM. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Hormones are implicated in various types of cancer, however, several aspects of steroid activity on carcinogenesis remain elusive. Recent progress has made it possible for us to directly study the biological mechanisms of disease development, including hormone−cancer relationships, from numerous viewpoints, from numerous viewpoints, including genome abnormalities. One tool is comparative genomic hybridization array (aCGH). Furthermore, it is possible to identify the so-called “cancer signature” by gene expression profiling, which provides new information about the role of steroids on carcinogenesis. DNA mutations and gene expression abnormalities may be associated with hormone-related cancer. The recent discovery of microRNA provides new opportunities for understanding the fine regulation of gene expression in cancer cells, and the role of microRNA in the relationship between hormones and cancer. From these experimental models we should be able to rapidly develop translation-to-treatment protocols. The final goal should be to design specific labs on a microchip for prognosis and therapy of individual patients. While in clinical research there is renewed attention to stratification of patients, especially those at high risk. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) patients are susceptible to tumor development. In the present study we describe a child with NF1 and disseminated neuroblastoma whose death resulted from disease progression. The mother had café-au-lait spots suggesting a familial NF1. Neuroblastoma cells showed MYCN amplification and chromosome 1p36 deletion, common features associated with tumor progression in this malignancy. The NF1 gene displayed a germline T --> C transition of intron 14 in both the proband and mother DNA. This mutation, not yet previously described, occurs in a splicing donor site and produces a new mRNA variant observed together with normal NF1 mRNA. Furthermore, the SSCP analysis of the NF1 gene in tumor cells showed a somatic deletion encompassing the intron 26 and 27b of the paternal NF1 allele. Hence, neuroblastoma cells displayed both somatic and germline mutation of the NF1 gene. Our data suggest that, although rare, neuroblastoma in patients with NF1 may display homozygous gene inactivation., (Copyright 2003 Wiley-Liss, Inc.)