Segmental chromosomal alterations have prognostic impact in neuroblastoma: A report from the INRG project

1] INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Institut Curie, Paris, France [2] Département d'Oncologie Pédiatrique, Institut Curie, 26 rue d'Ulm, Cedex 05, Paris 75248, France.
British Journal of Cancer (Impact Factor: 4.84). 09/2012; 107(8):1418-22. DOI: 10.1038/bjc.2012.375
Source: PubMed


In the INRG dataset, the hypothesis that any segmental chromosomal alteration might be of prognostic impact in neuroblastoma without MYCN amplification (MNA) was tested.

The presence of any segmental chromosomal alteration (chromosome 1p deletion, 11q deletion and/or chromosome 17q gain) defined a segmental genomic profile. Only tumours with a confirmed unaltered status for all three chromosome arms were considered as having no segmental chromosomal alterations.

Among the 8800 patients in the INRG database, a genomic type could be attributed for 505 patients without MNA: 397 cases had a segmental genomic type, whereas 108 cases had an absence of any segmental alteration. A segmental genomic type was more frequent in patients >18 months and in stage 4 disease (P<0.0001). In univariate analysis, 11q deletion, 17q gain and a segmental genomic type were associated with a poorer event-free survival (EFS) (P<0.0001, P=0.0002 and P<0.0001, respectively). In multivariate analysis modelling EFS, the parameters age, stage and a segmental genomic type were retained in the model, whereas the individual genetic markers were not (P<0.0001 and RR=2.56; P=0.0002 and RR=1.8; P=0.01 and RR=1.7, respectively).

A segmental genomic profile, rather than the single genetic markers, adds prognostic information to the clinical markers age and stage in neuroblastoma patients without MNA, underlining the importance of pangenomic studies.

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Available from: Susan L Cohn, Feb 19, 2014
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    • "In addition, some studies have shown that deletions at the chromosomal regions 3p, 4p, 9p, and 12p, which do occur at low frequency, can have prognostic impact (35, 49, 50). Recent publications clearly demonstrate the potential of genome-wide approaches to further refine the prognostic accuracy of somatically acquired chromosomal alterations (18, 35, 51–54), and numerous studies have demonstrated that in tumors without MNA, SCAs are frequently associated with clinically aggressive disease – for a summary see, e.g., Ref. (12). However, as already briefly discussed, the influence of SCAs on tumor behavior can differ in different age groups. "
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    ABSTRACT: Neuroblastoma serves as a paradigm for applying tumor genomic data for determining patient prognosis and thus for treatment allocation. MYCN status, i.e., amplified vs. non-amplified, was one of the very first biomarkers in oncology to discriminate aggressive from less aggressive or even favorable clinical courses of neuroblastoma. However, MYCN amplification is by far not the only genetic change associated with unfavorable clinical courses. So called "segmental chromosomal aberrations," (SCAs) i.e., gains or losses of chromosomal fragments, can also indicate tumor aggressiveness. The clinical use of these genomic aberrations has, however, been hampered for many years by methodical and interpretational problems. Only after reaching worldwide consensus on markers, methodology, and data interpretation, information on SCAs has recently been implemented in clinical studies. Now, a number of collaborative studies within COG, GPOH, and SIOPEN use genomic information to stratify therapy for patients with localized and metastatic disease. Recently, new types of DNA based aberrations influencing the clinical behavior of neuroblastomas have been described. Deletions or mutations of genes like ATRX and a phenomenon referred to as "chromothripsis" are all assumed to correlate with an unfavorable clinical behavior. However, these genomic aberrations need to be scrutinized in larger studies applying the most appropriate techniques. Single nucleotide polymorphism arrays have proven successful in deciphering genomic aberrations of cancer cells; these techniques, however, are usually not applied in the daily routine. Here, we present an ultra-high density (UHD) SNParray technique which is, because of its high specificity and sensitivity and the combined copy number and allele information, highly appropriate for the genomic diagnosis of neuroblastoma and other malignancies.
    Frontiers in Oncology 08/2014; 4:202. DOI:10.3389/fonc.2014.00202
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    • "Statistical analysis of the quantitative data of fibers, GAGs, tumor cells, and immune system markers compared with the current parameters used to predict risk of relapse (stage, age, histopathology, state of MYCN oncogene, state of 11q region, overall genomic profile, and ploidy) (72–74) and other genetic markers of prognostic interest in a subset of 78 primary neuroblastic tumors has already been published by our group, and highlights the interest of studying ECM in neuroblastic tumors (50). The fact that ECM elements differ depending on the characteristics of the tumors and, more interestingly, the fact that the characteristics of ECM elements are related to prognosis (relapse or overall survival) advocates on behalf of the regulatory role of ECM biotensegrity in tumor progression. "
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    ABSTRACT: Cells have the capacity to convert mechanical stimuli into chemical changes. This process is based on the tensegrity principle, a mechanism of tensional integrity. To date, this principle has been demonstrated to act in physiological processes such as mechanotransduction and mechanosensing at different scales (from cell sensing through integrins to molecular mechanical interventions or even localized massage). The process involves intra- and extracellular components, including the participation of extracellular matrix (ECM) and microtubules that act as compression structures, and actin filaments which act as tension structures. The nucleus itself has its own tensegrity system which is implicated in cell proliferation, differentiation, and apoptosis. Despite present advances, only the tip of the iceberg has so far been uncovered regarding the role of ECM compounds in influencing biotensegrity in pathological processes. Groups of cells, together with the surrounding ground substance, are subject to different and specific forces that certainly influence biological processes. In this paper, we review the current knowledge on the role of ECM elements in determining biotensegrity in malignant processes and describe their implication in therapeutic response, resistance to chemo- and radiotherapy, and subsequent tumor progression. Original data based on the study of neuroblastic tumors will be provided.
    Frontiers in Oncology 03/2014; 4:39. DOI:10.3389/fonc.2014.00039
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    • "Chromosome 1p36 is known to be deleted in ca. 30% of primary NB tumors, being one of the most common somatic cytogenetic abnormalities of recognizable prognostic significance [1,2]. Accordingly, it has been proposed as the putative locus for NB TSG, however so far no major NB predisposition gene has been identified in this region [3]. "
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    ABSTRACT: MYCN oncogene amplification is the most important prognostic factor in neuroblastoma. 25% neuroblastoma tumors have somatic amplifications at this locus but little is known about its constitutional aberrations and their potential role in carcinogenesis. Here, we have performed an array-CGH and qPCR characterization of two patients with constitutional partial 2p trisomy including MYCN genomic region. One of the patients had congenital neuroblastoma and showed presence of minute areas of gains and losses within the common fragile site FRA2C at 2p24 encompassing MYCN. The link between 2p24 germline rearrangements and neuroblastoma development was reassessed by reviewing similar cases in the literature. It appears that constitutional rearrangements involving chromosome 2p24 may play role in NB development.
    Molecular Cytogenetics 10/2013; 6(1):43. DOI:10.1186/1755-8166-6-43 · 2.14 Impact Factor
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