Primary mediastinal germ cell tumors (M-GCTs) represent a heterogeneous group of tumors that varies with regard to age at presentation, histologic differentiation, and outcome. We retrospectively analyzed archival tissue samples of mediastinal mature and immature teratomas (n = 15) and malignant nonseminomatous M-GCTs (n = 20) with comparative genomic hybridization (CGH). The aim of this study was to define distinct genetic subgroups of M-GCT among the pediatric cohort that may differ in their clinical behavior and prognosis. All pure teratomas showed normal CGH profiles. Malignant M-GCTs in infants and children < 8 years old most frequently showed a gain of 1q, 3, and 20q and a loss of 1p, 4q, and 6q. Gain of 12p and sex chromosomal abnormalities were not observed in this age group. In contrast, the gain of 12p was the most common aberration in M-GCTs that arose in children > or = 8 years old. Additional recurrent changes included the loss of chromosome 13 and the gain of chromosome 21. All ten adolescents with malignant M-GCT were male, and five showed a gain of the X chromosome. In two of these five patients, Klinefelter syndrome was confirmed by cytogenetic analysis or by fluorescence in situ hybridization (FISH). In conclusion, CGH analysis of M-GCTs defines distinct genetic subgroups. Mediastinal teratomas show no genetic gains or losses. Malignant M-GCTs in children < 8 years old show the same pattern of gains and losses identified in sacrococcygeal and testicular GCTs at this age, and they lack sex-chromosomal abnormalities. Malignant M-GCTs in children > or = 8 years old show the same genetic profile previously reported in gonadal GCTs at this age. In addition, approximately 50% demonstrate a gain of the X chromosome, consistent with Klinefelter syndrome. Cooperative group studies reveal a significantly better prognosis of malignant M-GCT arising in infants compared to that in adolescents, suggesting that these genetic differences are associated with differences in clinical behavior.

We correlate chromosomal changes in medulloblastomas with histologic subtype, reporting the analysis of 33 medulloblastoma specimens by comparative genomic hybridization, and a subset by fluorescence in situ hybridization. Of the 33 tumors, 5 were desmoplastic/nodular, 10 were histologically classic, and 18 were large cell/anaplastic. Chromosomal gains and losses were more common in anaplastic medulloblastomas than in non‐anaplastic ones. We identified 4 medulloblastomas with c‐myc amplification and 5 medulloblastomas with N‐myc amplification; all 9 were of the large cell/anaplastic subtype. Additional regions with high level gains included 2q14‐22, 3p23, 5p14‐pter, 8q24, 9p22‐23, 10p12‐pter, 12q24, 12p11‐12, 17p11‐12, and Xp11. The majority of these high level gains occurred in anaplastic cases. We also found loss of chromosome 17p in 7 large cell/anaplastic cases but no non‐anaplastic medulloblastomas. Finally, we detected a significantly increased overall number of chromosomal alterations in large cell/anaplastic medulloblastomas (6.8/case) compared to non‐anaplastic ones (3.3/case). These findings support an association between myc oncogene amplification, 17p loss, and large cell/anaplastic histology.

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The molecular signaling pathways mediating human germ cell tumor (GCT) formation and progression are poorly understood despite a large number of studies detailing recurrent cytogenetic abnormalities. Germ cell tumors consist of multiple histologic subtypes and can also be divided into infantile/childhood or adolescent/adult tumors as well as gonadal or nongonadal sites of origin. All of these parameters are important in defining clinical outcome and in understanding the pathogenesis of these tumors. We utilized complementary DNA (cDNA) microarray analysis to identify differences in signal transduction pathways between 2 histologic subtypes of malignant ovarian GCTs (dysgerminomas versus ovarian endodermal sinus tumors). Hierarchical cluster analysis using only the genes involved in Wnt/beta-catenin signaling was able to distinguish these 2 tumor subtypes from each other. Wnt13 and beta-catenin showed significant differential expression patterns between the 2 tumor subtypes, and the results were confirmed by semiquantitative reverse transcriptase-polymerase chain reaction. Additional GCTs were studied for the expression of other members of Wnt/beta-catenin signaling, including Wnt13, frizzled, disheveled, low-density lipoprotein receptor-related protein 6, and beta-catenin. Differential expression levels were identified for several histologic subtypes of human GCTs. Finally, we prepared tissue microarrays containing GCTs from 83 different patients and demonstrated high levels of beta-catenin protein expression in 100% and nuclear accumulation in approximately 50% to 70% of all endodermal sinus tumors and immature teratomas (ITs). This pattern was independent of the patient's age. No nuclear accumulation of beta-catenin was observed in germinomas, embryonal carcinomas, or choriocarcinomas. These results indicate that activation of Wnt/beta-catenin signaling plays an important role in the pathogenesis of 2 histologic subtypes of human GCTs.

These studies will help guiding further investigations elucidating the role of putative tumor suppressor genes at e.g. 1p36 and 6q. In addition, further studies incorporated in prospective therapeutic protocols are necessary to evaluate the prognostic relevance of specific genetic aberrations.