Pediatric primary central nervous system germ cell tumors of different prognosis groups show characteristic miRNome traits and chromosome copy number variations.
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.
Wang
Hsei-Wei
HW
School of Life Sciences, Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
Wu
Yu-Hsuan
YH
Hsieh
Jui-Yu
JY
Liang
Muh-Lii
ML
Chao
Meng-En
ME
Liu
Da-Jung
DJ
Hsu
Ming-Ta
MT
Wong
Tai-Tong
TT
D016543:Central Nervous System Neoplasms / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D056915:DNA Copy Number Variations; D004273:DNA, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D023281:Genomics / Q000379:methods; D006801:Humans; D000090062:Kruppel-Like Factor 4; D035683:MicroRNAs / Q000235:genetics*; D009373:Neoplasms, Germ Cell and Embryonal / Q000175:diagnosis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D013624:Taiwan
D004273:DNA, Neoplasm; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D035683:MicroRNAs