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:Background: Recent data demonstrated efficacy of immune checkpoint inhibitors in advanced OCCC, but little is known about the immune microenvironment of these tumours and its impact on outcomes. We studied the expression of a panel of immune response genes in OCCC to identify the presence and prognostic relevance of irGES in these tumours. Methods: Immune response gene profiling was performed on 96 FFPE OCCC tumour samples with matched clinical outcomes, collected from the National University Hospital, Singapore between 2003 – 2016, using the nanoString nCounter PanCancer Immune Profiling Panel. Unsupervised hierarchical clustering analysis was performed to stratify OCCCs to derive the irGES profiles. Upregulation of specific genes of interest at the protein level and the status of mismatch repair (MMR) and ARID1A were validated using immunohistochemistry (IHC). Results: Total of 74/84 samples were successfully profiled. Median age at diagnosis was 53 yrs. 41 (55.4%) were stage 1, 7 (9.5%) stage 2, 24 (32.4%) Stage3, 2 (2.7%) stage 4. 64/74 (86.5%) of patients received adjuvant chemotherapy post debulking surgery with 38% recurrence rate (median PFS 27 months). Median follow up was 36 months. Based on irGES, 4 distinct molecular subgroups of OCCCs were identified. G1 was hallmarked by NK cell markers and PD-1 expression (PD-1 high), G2 by increased CTLA-4 expression, G3 by upregulation of genes associated with immunogenicity and antigen presentation, and G4 by increased levels of pro - angiogenic genes. The PD-1 high group was observed to have significantly poorer PFS (median PFS 20 months vs 68 months, p= 0.011) and a trend towards poorer OS when compared with G2/3/4 (median OS 38.8 months vs undefined, p = 0.0501). The pro - angiogenic (G4) carried the best prognosis (median PFS 108 months vs 26 months, p= 0.0515; median OS undefined, p= 0.0726). This difference in OS and PFS was consistently observed between stage 1 and non-stage 1 pts (hazard ratio 5.856 and 5.659, p < 0.0001, respectively). Significant correlation was observed between gene and protein expression of tumour PD-1, tumour and stromal PD-L1, and tumour IL-6 using IHC (p < 0.0001 for all comparisons). 6 (8.1%) pts were MMR deficient and there was no significant association between ARID1A and MMR expression across each irGES groups. Conclusion: OCCCs are heterogeneous and can be classified into 4 molecular subgroups based on their irGES profiles representing distinct clinicopathological characteristics and prognostic outcomes. If validated in larger datasets, these signatures may serve to guide clinical trial design and personalized treatment for OCCC pts.

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.

Dataset Information

CaArray_lavar-00111: SPECIFIC GENE EXPRESSION PROFILES ASSOCIATED WITH INFANT DISSEMINATED NEUROBLASTOMA

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