Germ Cell Tumors
Central nervous system (CNS) germ cell tumors (GCTs) tumors remain one of the less explored pediatric brain tumors owing to their low incidence and a favored non-surgical treatment approaches in the Western countries. Moreover, around 10% of pure germinomas recur 5 years or more after the initial conventional therapy, and a significant proportion of non-germinomatous germ cell tumors (NGGCTs) are incurable, despite aggressive multidisciplinary treatment approaches. Additionally, approximately 30 to 40% of CNS GCTs will not achieve a complete or partial response after initial induction chemotherapy, necessitating either further surgery, chemotherapy, or higher dose/volume of irradiation.
Biology of GCTs has not been unraveled until recently – several groups have reported that alterations in the KIT signaling pathway play a major role in the development of GCTs. The Japanese investigators reported on mutually exclusive somatic mutations being detected in KIT and RAS, which were observed in 60% of pure germinomas compared to only 8.6% in NGGCTs. These results strongly suggest that activation of the KIT-driven Mitogen-activated protein kinase (MAPK) pathway plays an important role in the development of intracranial germinomas. Dr. Ching Lau’s group in the US analyzed 62 cases by SNP array and expression array. KIT/RAS signaling pathway was found to be frequently mutated in over 50% of IGCTs including novel recurrent somatic mutations in KIT, its downstream mediators KRAS and NRAS, and its negative regulator CBL. Novel somatic alterations in the AKT/mTOR pathway included copy number gain of the AKT1 locus at 14q32.33 in 19% of patients, with corresponding upregulation of AKT1 expression. However, the impact of MAPK/PI3K pathway mutations on the clinical course of CNS GCT patients remains uncertain. Ichimura et al., performed whole exome sequencing in 41 pairs of GCTs followed by targeted sequencing of 41 selected genes in a total of 124 CNS GCTs. Mutually exclusive mutations of genes involved in the MAPK pathway were most common (48.4 %), typically in KIT (27.4 %), followed by those in the PI3K pathway (12.9 %), particularly in mTOR (6.5 %). Survival data were available for 120 patients out of 123 primary CNS GCTs. When the patients’ survival was compared with the mutation status of gene along the MAPK or PI3K pathways, no statistically significant difference in survival was found. There was a tendency for shorter progression-free (PFS) and overall survival (OS) in patients with PI3K/mTOR pathway alterations, either among pure germinomas or all tumors, but not in NGGCTs. Wang et al., did report significant enrichment of novel and rare germline variants in JMJD1C, a histone demethylase and coactivator of the androgen receptor, among Japanese GCT patients. However, the frequency of such germline mutation in non-Japanese patients or its association with developing CNS GCTs hasn’t been tested.
On the other hand, the utility of the conventional body fluid protein biomarkers AFP and HCGβ for diagnosis and follow-up is restricted to specific GCT subtypes. Hence, body fluid biomarkers that offer greater sensitivity and specificity for diagnosing and/or monitoring CNS GCTs would be of major clinical benefit. MicroRNAs (miRNAs) from the miR–371–373 and miR–302/367 clusters are overexpressed in all GCTs, and some of these miRNAs show elevated serum levels at diagnosis. A method for miRNA quantification in the serum and CSF that enabled sample adequacy assessment and reliable data normalization was developed. This has shown high sensitivity/specificity for diagnosing pediatric extracranial malignant GCT, allowed early detection of relapse of a testicular mixed malignant GCT, and distinguished intracranial malignant GCT from intracranial non-GCT tumors at diagnosis. This method needs to be tested in a prospective setting for diagnosis and monitoring of CNS GCTs.
Major aims and focus of the GCT working group:
Conduct the first prospective study to investigate the biology of CNS GCTs and to elucidate the role of the genetic aberrations identified in these multiple reports as a prognostic marker. Consequently, we will extend our knowledge of tumor biology, identify novel biological markers and therapeutic targets for the subset of patients that is refractory to therapy, and develop combined clinical and biological risk stratification algorithms for patients with CNS GCTs. This should ultimately lead to appropriately tailored therapy and allow reduction of treatment in an effort to decrease late-effects. Additionally, there are no clinical trials available in North America for relapsed/refractory CNS GCTs; therefore, another main goal of the PNOC working group will be to initiate a clinical trial with novel targeted therapies for this group of patients, which we believe will pave the way to incorporate targeted therapies in the treatment of newly-diagnosed patients.