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

Hsei-Wei Wang,Meng-En Chao,Da-Jung Liu,Jui-Yu Hsieh,Muh-Lii Liang,Tai-Tong Wong,Ming-Ta Hsu,Yu-Hsuan Wu

doi:10.1186/1471-2164-11-132

Abstract

BackgroundIntracranial 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.ResultsWe 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/β-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.ConclusionsOur 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.

Highlights

Intracranial pediatric germ cell tumors (GCTs) are rare and heterogeneous neoplasms and vary in histological differentiation, prognosis and clinical behavior
Clinical aspects of primary pediatric central nervous system (CNS) GCTs examined In our series of 176 cases of primary pediatric CNS GCTs, 58.5% were germinoma and 41.5% were nongerminomatous GCTs (NGGCTs)
Subtypes of NGGCTs included mature teratomas (5.1%), various nongerminomatous malignant germ cell tumors (NGMGCTs) including immature teratomas, mixed GCTs, pure yolk sac tumors (YST), and tumors diagnosed by tumor markers (35.2%), and unclassified GCTs (1.7%) (Additional file 1-A) The 5-year, 10-year and 15-year overall survival rates for the germinomas and NGMGCTs were 82.2%, 74.5% and 74.5% for the germinomas and 66.1%, 45.4% and 30.3% for the NGMGCTs

Summary

Introduction

Intracranial pediatric germ cell tumors (GCTs) are rare and heterogeneous neoplasms and vary in histological differentiation, prognosis and clinical behavior. The reported incidence of primary germ cell tumors (GCTs) of central nervous system (CNS) in children is significantly higher in Taiwan, Japan and Korea compared to Western countries. According to histological differentiation, related tumor markers, and secreted protein markers, these tumors can be classified into germinomas and nongerminomatous GCTs (NGGCTs), the latter including embryonal carcinoma (EC), yolk sac tumors (YST), choriocarcinoma (CC), teratoma (mature teratoma, immature teratoma, or immature teratoma with malignant differentiation) and mixed GCTs [6]. For NGGCTs, except for benign mature teratoma, all of the other tumors present with diverse malignancies and therapeutic sensitivities when compared to germinomas and are grouped together as nongerminomatous malignant GCTs (NGMGCTs). YST and CC correspond to the extra-embryonic differentiation along mesoblast and trophoblast lines, respectively This contrasts with teratomas, which consist of differentiated derivatives that include all three germ layers with or without incompletely differentiated tissue elements, like neuroepithelium, which resembles fetal tissue. CNS GCTs often present with more than one histological component and are classified as mixed GCTs [7,10,11]

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