Germ cell tumors (GCTs) of the CNS are rare neoplasms affecting mainly adolescent and young adults with a peak onset around puberty. GCTs are classified as i) germinomas, ii) embryonal carcinomas, iii) yolk sac tumors, iv) choriocarcinomas, v) teratomas, and vi) mixed germ cell tumors. Germinoma are the most common while the remaining are collectively referred to as non-germinomatous GCT (NGGCT). Importantly, some tumors are composed of two or more subtypes, most commonly germinoma and teratoma, and are termed “mixed GCTs.” ¹ KIT/RAS and mTOR signaling pathway aberrations play an important role in the pathogenesis of intracranial GCTs. ² Genomic instability is common in GCTs with gains of chromosomes 21q, X, 12p, and 1q as well as losses of 5q, 11q, and 13q frequently being observed. ^3,4 12p gains, including i(12p), have shown prognostic value and are predominantly observed in NGGCTs. ⁵
Recently, three distinct subtypes of GCT were uncovered using transcriptional analysis with unique genomic and clinical profiles: i) immune-hot, ii) MYC/E2F, and iii) SHH. The immune-hot and MYC/E2F subgroups were highly enriched for germinomas and showed elevated activation for immune-associated pathways and enrichment for cell cycle-associated pathways, respectively. In contrast, the SHH subgroup consisted of both germinomas and NGGCT, with the majority of NGGCTs classifying within this group. The SHH subgroup, as its name suggests, was enriched for genes associated with the SHH- and epithelial to mesenchymal transition- signaling pathways. In addition to the well described somatic variants in KIT, KRAS, BCORL1, RRAS2, CBL, and BRAF, new drivers identified included those in USP28 and CRKL. Furthermore, high-level copy number amplifications of KRAS and CRKL were also revealed as a previously underscribed mechanism of disease.  ⁶