Hypomethylated X Chromosome Gain and Rare Isochromosome 12p in Diverse Intracranial Germ Cell Tumors

Twenty-five primary intracranial germ cell tumors (11 germinomas, 5 teratomas, 5 mixed teratomas-germinomas, 1 mixed choriocarcinoma-teratoma, 1 yolk sac tumor, 1 mixed yolk sac tumor-teratoma, and 1 embryonal carcinoma; from 24 males and 1 female) were studied by fluorescence in situ hybridization with probes to the X and Y chromosomes, chromosome 12p, the CDKN2A/p16 gene, and chromosome 13q—loci previously noted to be altered in either intracranial or systemic germ cell tumors. An increased number of X chromosomes, typically 1 extra copy, was observed in 23 of 25 cases (92%), with methylation-sensitive PCR demonstrating that the additional X chromosomes were hypomethylated in 13 of 16 (81%) studied tumors. Five cases (20%) had increased copy numbers of 12p (including tumors with isochromosome 12p), and 3 (12%) had 13q loss. No tumors had CDKN2A/p16 deletion or mutation, and 16 of 25 (64%) were positive for p16 expression by immunohistochemistry. Genetic alterations such as isochromosome 12p, 13q loss and CDKN2A/p16 are therefore not common in intracranial germ cell tumors. However, gains of hypomethylated, active X chromosomes occur in nearly all intracranial germ cell tumors, regardless of histological subtype. Along with the observed male predominance of intracranial germ cell tumors and the predisposition in Klinefelter syndrome patients for these lesions, the data argue strongly that sex chromosome aberrations, rather than isochromosome 12p, are integral to intracranial germ cell tumorigenesis