Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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High-resolution, genome-wide analysis of human metastatic neuroblastoma samples by array-Comparative Genomic Hybridization (aCGH)

ABSTRACT: Less than 30% of children with high-risk (HR) metastatic neuroblastoma (NB) show a long survival (Pearson 2000). In order to identify novel molecular prognostic markers useful to better predict patientsM-bM-^@M-^Y relapse risk estimation, we performed genome- and/or transcriptome-wide analyses of 129 stage 4 HR-NBs. This is the largest study for this NB subtype. Children older than 1 year of age at diagnosis were categorized as M-bM-^@M-^\short-survivorsM-bM-^@M-^] (dead of disease within 5 years from diagnosis) and M-bM-^@M-^\long-survivorsM-bM-^@M-^] (alive with an overall survival time > 5 years). A significant correlation of patient survival with the presence of small number of segmental copy number aberrations (CNA < 3) was observed. Thus, within the group of stage 4 HR-NBs, we identified a specific subgroup of patients (those with highest number of CNA) that have a higher risk of progression/recurrence. The complex genomic pattern is an independent prognostic marker, since MYCN oncogene amplification only affects the predictive value of single CNA (i.e., 1p loss, 17q gain). Integrative analysis of genomic and expression signatures demonstrated that fatal outcome is associated with loss of cell cycle control and with progression of tumor due to deregulation of Rho GTPase signaling and genes related to cell motility. Tumors with MYCN amplification showed a lower chromosome instability compared to MYCN-single copy NBs (P=0.0008), dominated by 17q gain and 1p loss. Moreover, our results suggest that the MYCN amplification mainly drives the disruption of neuronal differentiation and the reduction of cell adhesion process involved in tumor invasion and metastasis. For array-CGH profiling, we analyzed 91 samples of metastatic neuroblastomas. All patients were classified as stage 4 and they were older than 1 year of age at time of diagnosis. Regarding the clinical course, 46 were short-survivors (dead of disease within 60 months from diagnosis. Deaths due to toxicity were censored) and 45 were long-survivors (alive with an overall survival time > 60 months). This submission consists of 22 new samples and 69 other cases previously deposited in GEO under Series accessions GSE14109 and GSE25771.

ORGANISM(S): Homo sapiens

SUBMITTER: PAOLA SCARUFFI

PROVIDER: E-GEOD-35953 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

High genomic instability predicts survival in metastatic high-risk neuroblastoma.

Stigliani Sara S Coco Simona S Moretti Stefano S Oberthuer Andrè A Fischer Mattias M Theissen Jessica J Gallo Fabio F Garavent Alberto A Berthold Frank F Bonassi Stefano S Tonini Gian Paolo GP Scaruffi Paola P

Neoplasia (New York, N.Y.) 20120901 9

We aimed to identify novel molecular prognostic markers to better predict relapse risk estimate for children with high-risk (HR) metastatic neuroblastoma (NB). We performed genome- and/or transcriptome-wide analyses of 129 stage 4 HR NBs. Children older than 1 year of age were categorized as "short survivors" (dead of disease within 5 years from diagnosis) and "long survivors" (alive with an overall survival time ≥ 5 years). We reported that patients with less than three segmental copy number ab ...[more]

PMID: 23019414

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Project description:Neuroblastoma (NB) is an aggressive tumor that affects both infants and children. The disease outcome is greatly influenced by age of patient, stage, chromosome copy number aberrations (CNAs) and gene expression abnormalities. We analyzed, by microarray technology, genome and transcriptome of 3 groups of tumors of patients with metastatic disease: G1, stage 4S and MYCN single copy; G2, stage 4 younger than 18 months of age, MYCN single copy with no disease progression and G3, stage 4, older than 19 months, with unfavorable outcome. We found an accumulation of structural copy number aberrations (CNAs) in G3 whereas G1 tumors had mostly numerical (N) CNAs and G2 showed an intermediate behavior. Pair wise comparisons demonstrated that the average of N CNAs significantly decreased from G1 to G2 to G3 (9.6 G1 < 7.2 G2 < 3.6 G3); in contrast S CNAs significantly increased in G3 (0.7 G1 < 3.7 G2 < 7.0 G3). Interestingly, we observed several intra-chromosomal rearrangements in G3 tumors on chromosomes not usually involved in NB. Excluding MYCN amplified tumors by G3 we found a high frequency of S CNAs in this group. Gene expression analysis showed a deregulation of downstream genes of Ras and Rho signaling pathway among the 3 groups. It has been also observed a progressive switch off of development and adhesion genes and a switch on of cell cycle genes from G1 to G2 to G3. Moreover, the telemorase genes were significantly expressed in G3 with respect to remaining groups. Present data show an accumulation of S CNAs from stage 4S to 4. The deregulation of genes Rho/Ras pathway may explain the increase of tumor aggressiveness from G1 to G2 to G3. The increase of cell cycle and telomerase genes expression associated with G3 would provide unlimited replicative potential for these tumors and may be responsible for accumulation of S CNAs. Finally, we can argue that accumulation of structural aberrations and gene deregulation is age-dependent and it is associated with a more aggressive tumor phenotype. We analyzed 133 samples of metastatic neuroblastoma from patients divided into three groups: G1 49 patients stage 4S and MYCN single copy; G2 37 patients stage 4 younger than 18 months of age at diagnosis, MYCN single copy with no disease progression; G3 47 patients stage 4 older than 19 months of age at diagnosis, with unfavorable outcome.

Project description:Establishment and subsequent validation of a aCGH protocol for WGA (whole genome amplification) products originating from single cell or low amount of starting material (i.e. microdissected FFPE tissue samples). The establishment of the protocol involved testing of three DNA labeling protocols. Two labeling protocols were designed specifically for Ampli1(TM) WGA products. Additionally random primed isothermal (Klenow-based) labeling approach was tested (MM-CM-6hlendick et al., PLoS One. 2013 Jun 25;8(6):e67031.). In addition two different types of reference samples were tested and reference based on single-cell WGA products was chosen as most suitable in the end. The validation of the protocol assessed the following aspects: (1) performance of the protocol on primary and reamplified WGA products, (2) accuracy of the protocol in term of sensitivity of the CNA detection, (3) accuracy in terms of recapitulation of complex patterns of CNAs, (4) accuracy in terms of quantitative assessment of the CNAs, (5) ability to detect genomic heterogeneity of single cells (obtained either from in vitro cultures or from clinical patient material), (6) ability to detect minimal regions of aberration within a panel of disseminated cancer cells and corresponding tumor tissues. Establishment and validation of the single-cell aCGH protocol: two condition experiment (i.e. PCR-based labeling technique 1 vs. PCR-based labeling technique 2; PCR-based labeling technique 2 vs. random-primed isothermal (Klenow) labeling approach; reference DNA from cell pool WGA product vs. reference DNA from single-cell WGA products). Validation of the protocol: comparison of the CNA profiles between single-cell WGA products and corresponding bulk DNA. Analysis of the DCC and corresponding FFPE tumor tissue samples: single-condition experiment performed on samples collected at different stages of the disease (DCCs from bone marrow) and/or from different sites (primary tumor-breast; metastasis-lymph nodes; DCCs-bone marrow). Microarray data is corresponding data depicted in the paper manuscript titled: Reliable single cell array CGH for clinical samples

Dataset Information

High-resolution, genome-wide analysis of human metastatic neuroblastoma samples by array-Comparative Genomic Hybridization (aCGH)

Publications

High genomic instability predicts survival in metastatic high-risk neuroblastoma.

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