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Pediatric primary central nervous system germ cell tumors of different prognosis groups show characteristic miRNome traits and chromosome copy number variations.

Wang HW, Wu YH, Hsieh JY, Liang ML, Chao ME, Liu DJ, Hsu MT, Wong TT - BMC Genomics (2010)

Bottom Line: Genes responsible for self-renewal (such as POU5F1 (OCT4), NANOG and KLF4) and the immune response were abundant in germinomas, while genes associated with neuron differentiation, Wnt/beta-catenin pathway, invasiveness and epithelial-mesenchymal transition (including SNAI2 (SLUG) and TWIST2) were abundant in NGMGCTs.Six genes (BANK1, CXCL9, CXCL11, DDIT4L, ELOVL6 and HERC5) within 4q13.3-4q28.3 were more abundant in germinomas.The genes, pathways and microRNAs identified have the potential to be novel therapeutic targets.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Life Sciences, Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.

ABSTRACT

Background: Intracranial pediatric germ cell tumors (GCTs) are rare and heterogeneous neoplasms and vary in histological differentiation, prognosis and clinical behavior. Germinoma and mature teratoma are GCTs that have a good prognosis, while other types of GCTs, termed nongerminomatous malignant germ cell tumors (NGMGCTs), are tumors with an intermediate or poor prognosis. The second group of tumors requires more extensive drug and irradiation treatment regimens. The mechanisms underlying the differences in incidence and prognosis of the various GCT subgroups are unclear.

Results: We identified a distinct mRNA profile correlating with GCT histological differentiation and prognosis, and also present in this study the first miRNA profile of pediatric primary intracranial GCTs. Most of the differentially expressed miRNAs were downregulated in germinomas, but miR-142-5p and miR-146a were upregulated. Genes responsible for self-renewal (such as POU5F1 (OCT4), NANOG and KLF4) and the immune response were abundant in germinomas, while genes associated with neuron differentiation, Wnt/beta-catenin pathway, invasiveness and epithelial-mesenchymal transition (including SNAI2 (SLUG) and TWIST2) were abundant in NGMGCTs. Clear transcriptome segregation based on patient survival was observed, with malignant NGMGCTs being closest to embryonic stem cells. Chromosome copy number variations (CNVs) at cytobands 4q13.3-4q28.3 and 9p11.2-9q13 correlated with GCT malignancy and clinical risk. Six genes (BANK1, CXCL9, CXCL11, DDIT4L, ELOVL6 and HERC5) within 4q13.3-4q28.3 were more abundant in germinomas.

Conclusions: Our results integrate molecular profiles with clinical observations and provide insights into the underlying mechanisms causing GCT malignancy. The genes, pathways and microRNAs identified have the potential to be novel therapeutic targets.

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Altered functional modules in the different pediatric GCT prognostic groups. (A-B) Gene set enrichment analysis according to the Gene Ontology (GO) classification. Probe sets differentiating good prognostic CNS GCTs from intermediate/poor prognostic CNS GCTs were subjected to the GO database search via the DAVID 2008 interface. The number of genes, gene symbols, their percentages and the p values for each category that show significance (p < 0.05) and are enriched in either the good (A) or the intermediate/poor (B) prognostic group are listed. (C) KEGG pathways significantly enriched in the TW NGMGCT genes. The number of genes, their percentages in terms of total genes, and the p values for pathways that are significantly over-represented (p < 0.05 by the DAVID 2008 tool) are listed. (D) Distribution of signature genes on the chromosome cytobands.
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Figure 3: Altered functional modules in the different pediatric GCT prognostic groups. (A-B) Gene set enrichment analysis according to the Gene Ontology (GO) classification. Probe sets differentiating good prognostic CNS GCTs from intermediate/poor prognostic CNS GCTs were subjected to the GO database search via the DAVID 2008 interface. The number of genes, gene symbols, their percentages and the p values for each category that show significance (p < 0.05) and are enriched in either the good (A) or the intermediate/poor (B) prognostic group are listed. (C) KEGG pathways significantly enriched in the TW NGMGCT genes. The number of genes, their percentages in terms of total genes, and the p values for pathways that are significantly over-represented (p < 0.05 by the DAVID 2008 tool) are listed. (D) Distribution of signature genes on the chromosome cytobands.

Mentions: The gene list outlined above gave us preliminary insights into the functional consequences of detected differential gene expression. To understand more about how the gene expression profiles might be correlated with pathogenesis and the various clinical phenotypes as well as to provide quantitative evidence, the signature mRNAs were subjected to a Gene Ontology (GO) database search [40] in order to find statistically overrepresented functional groups within the gene lists. The WebGestalt web tool [41] was applied to provide statistical analysis and visual presentation of the results. The GO categories of biological processes that were statistically overrepresented (p < 0.05) among genes of the germinoma group are shown in Figure 3A. Genes CHEK2 and HUS1, which are involved in the DNA damage checkpoint, were significantly overexpressed in germinomas (p = 3.45*10e-2; Figure 3A, panel 1). Another significant biological process associated with this group is related to the immune system processes (p = 2.64*10e-2; Figure 3A, panel 2, where the involved immune response genes are shown). Other predominant processes in the GP group include genes pertaining to reproduction (p = 2.74*10e-2) and male gonad development (p = 1.24*10e-2; Figure 3A, panel 3).


Pediatric primary central nervous system germ cell tumors of different prognosis groups show characteristic miRNome traits and chromosome copy number variations.

Wang HW, Wu YH, Hsieh JY, Liang ML, Chao ME, Liu DJ, Hsu MT, Wong TT - BMC Genomics (2010)

Altered functional modules in the different pediatric GCT prognostic groups. (A-B) Gene set enrichment analysis according to the Gene Ontology (GO) classification. Probe sets differentiating good prognostic CNS GCTs from intermediate/poor prognostic CNS GCTs were subjected to the GO database search via the DAVID 2008 interface. The number of genes, gene symbols, their percentages and the p values for each category that show significance (p < 0.05) and are enriched in either the good (A) or the intermediate/poor (B) prognostic group are listed. (C) KEGG pathways significantly enriched in the TW NGMGCT genes. The number of genes, their percentages in terms of total genes, and the p values for pathways that are significantly over-represented (p < 0.05 by the DAVID 2008 tool) are listed. (D) Distribution of signature genes on the chromosome cytobands.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2837036&req=5

Figure 3: Altered functional modules in the different pediatric GCT prognostic groups. (A-B) Gene set enrichment analysis according to the Gene Ontology (GO) classification. Probe sets differentiating good prognostic CNS GCTs from intermediate/poor prognostic CNS GCTs were subjected to the GO database search via the DAVID 2008 interface. The number of genes, gene symbols, their percentages and the p values for each category that show significance (p < 0.05) and are enriched in either the good (A) or the intermediate/poor (B) prognostic group are listed. (C) KEGG pathways significantly enriched in the TW NGMGCT genes. The number of genes, their percentages in terms of total genes, and the p values for pathways that are significantly over-represented (p < 0.05 by the DAVID 2008 tool) are listed. (D) Distribution of signature genes on the chromosome cytobands.
Mentions: The gene list outlined above gave us preliminary insights into the functional consequences of detected differential gene expression. To understand more about how the gene expression profiles might be correlated with pathogenesis and the various clinical phenotypes as well as to provide quantitative evidence, the signature mRNAs were subjected to a Gene Ontology (GO) database search [40] in order to find statistically overrepresented functional groups within the gene lists. The WebGestalt web tool [41] was applied to provide statistical analysis and visual presentation of the results. The GO categories of biological processes that were statistically overrepresented (p < 0.05) among genes of the germinoma group are shown in Figure 3A. Genes CHEK2 and HUS1, which are involved in the DNA damage checkpoint, were significantly overexpressed in germinomas (p = 3.45*10e-2; Figure 3A, panel 1). Another significant biological process associated with this group is related to the immune system processes (p = 2.64*10e-2; Figure 3A, panel 2, where the involved immune response genes are shown). Other predominant processes in the GP group include genes pertaining to reproduction (p = 2.74*10e-2) and male gonad development (p = 1.24*10e-2; Figure 3A, panel 3).

Bottom Line: Genes responsible for self-renewal (such as POU5F1 (OCT4), NANOG and KLF4) and the immune response were abundant in germinomas, while genes associated with neuron differentiation, Wnt/beta-catenin pathway, invasiveness and epithelial-mesenchymal transition (including SNAI2 (SLUG) and TWIST2) were abundant in NGMGCTs.Six genes (BANK1, CXCL9, CXCL11, DDIT4L, ELOVL6 and HERC5) within 4q13.3-4q28.3 were more abundant in germinomas.The genes, pathways and microRNAs identified have the potential to be novel therapeutic targets.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Life Sciences, Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.

ABSTRACT

Background: Intracranial pediatric germ cell tumors (GCTs) are rare and heterogeneous neoplasms and vary in histological differentiation, prognosis and clinical behavior. Germinoma and mature teratoma are GCTs that have a good prognosis, while other types of GCTs, termed nongerminomatous malignant germ cell tumors (NGMGCTs), are tumors with an intermediate or poor prognosis. The second group of tumors requires more extensive drug and irradiation treatment regimens. The mechanisms underlying the differences in incidence and prognosis of the various GCT subgroups are unclear.

Results: We identified a distinct mRNA profile correlating with GCT histological differentiation and prognosis, and also present in this study the first miRNA profile of pediatric primary intracranial GCTs. Most of the differentially expressed miRNAs were downregulated in germinomas, but miR-142-5p and miR-146a were upregulated. Genes responsible for self-renewal (such as POU5F1 (OCT4), NANOG and KLF4) and the immune response were abundant in germinomas, while genes associated with neuron differentiation, Wnt/beta-catenin pathway, invasiveness and epithelial-mesenchymal transition (including SNAI2 (SLUG) and TWIST2) were abundant in NGMGCTs. Clear transcriptome segregation based on patient survival was observed, with malignant NGMGCTs being closest to embryonic stem cells. Chromosome copy number variations (CNVs) at cytobands 4q13.3-4q28.3 and 9p11.2-9q13 correlated with GCT malignancy and clinical risk. Six genes (BANK1, CXCL9, CXCL11, DDIT4L, ELOVL6 and HERC5) within 4q13.3-4q28.3 were more abundant in germinomas.

Conclusions: Our results integrate molecular profiles with clinical observations and provide insights into the underlying mechanisms causing GCT malignancy. The genes, pathways and microRNAs identified have the potential to be novel therapeutic targets.

Show MeSH
Related in: MedlinePlus