Aim of the studyExamination of copy number changes in a group of intracranial germ cell tumors (GCTs) with particular focus on putative aberrations of the main genes coding SHh pathway proteins.Material and methodsThe study was performed on DNA isolated from fresh-frozen tumor tissue samples from eight GCTs, including six intracranial GCTs. The intracranial group consisted of three germinomas, two mature teratomas and one mixed germ cell tumor. Comparative genomic profiling analysis was carried out using microarray-CGH method (Cytosure ISCA UPD 4×180k, OGT). The results were analyzed with Feature Extraction (Agilent Technologies) and Nexus Copy Number (BioDiscovery) softwares.Results and conclusionsChromosomal aberrations were found in two intracranial germinomas. These tumors were characterized by complex genomic profiles encompassing chromosomes 7, 8, 9, 10, 11, 12, 16, 17 and 19. Common findings were gain at 12p13.33p11.1 of 35 Mbp and gain at 17q11.1q25.3 of 55 Mbp. In one tumor, also SHh (7q36.3), SMO (7q32.1) and GLI3 (7p14.1) copy gains occurred together with 9q21.11q34.3 loss, including PTCH1, all being elements of SHh signaling pathway. Moreover, both tumors showed various copy gain of genes being ligands, regulators, receptors or target genes of SHh (MTSS1; PRKACA and FKBP8) as well as gain of genes of SHh coopting WNT pathway (WNT3, WNT5B, WNT9B in both tumors; WNT16, WNT2 in pineal lesion). Further studies on larger group are needed to characterize SHh-related gene alterations in intracranial GCTs and for searching genotype-phenotype relations.

This article reports a case of a 7-year-old girl with Turner syndrome, treated with growth hormone (GH), who developed ovarian dysgerminoma. The patient karyotype was mosaic for chromosome Xq deletion: 46,X,del(X)(q22)/45,X. No Y chromosome sequences were present. Molecular studies revealed the presence of a driving mutation in exon 17 of the KIT gene in the neoplastic tissue, as well as Sonic-hedgehog (SHH) pathway activation at the protein level. The patient responded well to chemotherapy and remained in complete remission. This is the first case of dysgerminoma in a Turner syndrome patient with such oncogenic pathway.

Introduction: Germ cell tumours (GCTs) in the children comprise a group of tumours that originate from primordial germ cells but their pathogenesis is not clear. Intracranial GCTs represent a special subset of these paediatric neoplasms. Hedgehog (Hh) pathway gene status in GCTs is generally unexplored, while Hh signalling is involved in germ cell biology. Material and methods: Comparative genomic profiling analysis with a microarray-comparative genomic hybridization (CGH) + single nucleotide polymorphism (SNP) technique in a group of intracranial paediatric GCTs was performed. The analysis included evaluation of genes being ligands, receptors, regulators, effectors, and targets of Hh signalling. Results: Chromosomal aberrations were found in 62% of examined tumours, showing their heterogeneity. A number of private genomic imbalances were observed, but only a few recurrent ones. The most common numerical changes were trisomies 19, 21 and monosomies 13, 18 while the most frequent structural aberration was gain/ amplification of the chromosome 12p. The analysis of the gene status of Hh network elements showed imbalances in a proportion of tumours. PTCH1, GLI2, IHH and ZIC2 gene aberrations occurred most frequently. Moreover, six tumours had various copy gains or losses of several other genes involved in the pathway, including HHIP, GLI1, GLI3, DHH, SHH, SMO, PTCH2, and several genes from the WNT group. Interestingly, four cases showed losses of pathway repressors, with parallel gains of activators in two of them. Correlations with patho-clinical tumour features were not found, most probably due to the heterogeneity of the examined limited group. Conclusions: Our results show few genomic alterations related to the Hh signalling pathway genes in paediatric intracranial GCTs. Further analysis of Hedgehog pathway alterations can potentially disclose its biological significance and define new prognostic factors and/or therapeutic targets for high-risk patients.