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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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MiRNome analysis of childhood CNS GCTs. (A) Overall survival rates of GCTs of different histological subtypes. In total, 161 patients were followed up for up to 20 years. These were then subjected to Kaplan-Meier survival analysis. Numbers in parentheses are case numbers of each tumor subtype. Vertical lines indicate the censored survival observations. (B) Principal component analysis (PCA) using the filtered miRNAs (p < 0.05 and fold change ≧2). Each spot represents a single array. (C) A heat map shows the miRNAs enriched in the different prognostic groups. MiRNAs in red showed increased expression, while those in blue showed decreased. (D-E) Validation of miRNA array results by real-time PCR. The mean expression levels of the target miRNAs are compared to that of the U6 small nuclear RNA control. Results are expressed as the mean ± standard deviation (SD) (E). The miRNAs' array hybridization signals are also shown (D).
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Figure 1: MiRNome analysis of childhood CNS GCTs. (A) Overall survival rates of GCTs of different histological subtypes. In total, 161 patients were followed up for up to 20 years. These were then subjected to Kaplan-Meier survival analysis. Numbers in parentheses are case numbers of each tumor subtype. Vertical lines indicate the censored survival observations. (B) Principal component analysis (PCA) using the filtered miRNAs (p < 0.05 and fold change ≧2). Each spot represents a single array. (C) A heat map shows the miRNAs enriched in the different prognostic groups. MiRNAs in red showed increased expression, while those in blue showed decreased. (D-E) Validation of miRNA array results by real-time PCR. The mean expression levels of the target miRNAs are compared to that of the U6 small nuclear RNA control. Results are expressed as the mean ± standard deviation (SD) (E). The miRNAs' array hybridization signals are also shown (D).

Mentions: Kaplan-Meier estimator analysis and log-rank test revealed that the germinoma patients had a better overall survival than the NGMGCT patients (p = 0.0005; Figure 1A). Accordingly, therapeutic classification of the GCTs represents prognostic factor-based classification and management. However, the therapeutic classification of CNS GCTs is quite different between the CNS GCTs and extra-CNS GCTs, because of rareness of systemic metastasis of the CNS GCTs [9]. According to the clinical and therapeutic classification of CNS GCTs [9], in our series of CNS GCTs in children, 113 cases (63.6%), including 103 germinomas, 9 mature teratomas, and 1 mixed germinoma and mature teratoma, were categorized as members of the good prognostic group (GPG), 40 cases, including 12 immature teratomas and 19 mixed GCTs, were categorized as members of the intermediate prognostic group (IPG), and 14 cases, including 10 pure yolk sac tumors and 4 mixed GCTs dominated by yolk sac tumors, were categorized as members of the poor prognostic group (PGG) [9]. For the 21 cases that underwent genomic studies (Additional file 1-B), cases 1-12 could be categorized as members of the GPG and these included 9 pure germinomas, 2 mature teratomas, and 1 mixed germinoma- mature teratoma. Cases 13-18 could be categorized as members of the IPG and included 5 mixed GCTs and 1 immature teratoma. Cases 19-21 belonged to the PPG and included 3 mixed GCTs with YST component predominance (Additional file 1-B).


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)

MiRNome analysis of childhood CNS GCTs. (A) Overall survival rates of GCTs of different histological subtypes. In total, 161 patients were followed up for up to 20 years. These were then subjected to Kaplan-Meier survival analysis. Numbers in parentheses are case numbers of each tumor subtype. Vertical lines indicate the censored survival observations. (B) Principal component analysis (PCA) using the filtered miRNAs (p < 0.05 and fold change ≧2). Each spot represents a single array. (C) A heat map shows the miRNAs enriched in the different prognostic groups. MiRNAs in red showed increased expression, while those in blue showed decreased. (D-E) Validation of miRNA array results by real-time PCR. The mean expression levels of the target miRNAs are compared to that of the U6 small nuclear RNA control. Results are expressed as the mean ± standard deviation (SD) (E). The miRNAs' array hybridization signals are also shown (D).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: MiRNome analysis of childhood CNS GCTs. (A) Overall survival rates of GCTs of different histological subtypes. In total, 161 patients were followed up for up to 20 years. These were then subjected to Kaplan-Meier survival analysis. Numbers in parentheses are case numbers of each tumor subtype. Vertical lines indicate the censored survival observations. (B) Principal component analysis (PCA) using the filtered miRNAs (p < 0.05 and fold change ≧2). Each spot represents a single array. (C) A heat map shows the miRNAs enriched in the different prognostic groups. MiRNAs in red showed increased expression, while those in blue showed decreased. (D-E) Validation of miRNA array results by real-time PCR. The mean expression levels of the target miRNAs are compared to that of the U6 small nuclear RNA control. Results are expressed as the mean ± standard deviation (SD) (E). The miRNAs' array hybridization signals are also shown (D).
Mentions: Kaplan-Meier estimator analysis and log-rank test revealed that the germinoma patients had a better overall survival than the NGMGCT patients (p = 0.0005; Figure 1A). Accordingly, therapeutic classification of the GCTs represents prognostic factor-based classification and management. However, the therapeutic classification of CNS GCTs is quite different between the CNS GCTs and extra-CNS GCTs, because of rareness of systemic metastasis of the CNS GCTs [9]. According to the clinical and therapeutic classification of CNS GCTs [9], in our series of CNS GCTs in children, 113 cases (63.6%), including 103 germinomas, 9 mature teratomas, and 1 mixed germinoma and mature teratoma, were categorized as members of the good prognostic group (GPG), 40 cases, including 12 immature teratomas and 19 mixed GCTs, were categorized as members of the intermediate prognostic group (IPG), and 14 cases, including 10 pure yolk sac tumors and 4 mixed GCTs dominated by yolk sac tumors, were categorized as members of the poor prognostic group (PGG) [9]. For the 21 cases that underwent genomic studies (Additional file 1-B), cases 1-12 could be categorized as members of the GPG and these included 9 pure germinomas, 2 mature teratomas, and 1 mixed germinoma- mature teratoma. Cases 13-18 could be categorized as members of the IPG and included 5 mixed GCTs and 1 immature teratoma. Cases 19-21 belonged to the PPG and included 3 mixed GCTs with YST component predominance (Additional file 1-B).

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