New insights into germ cell tumor genomics

Abstract

Background: Testicular germ cell tumors (GCTs) represent the most common malignancy in young men. While GCTs represent a model for curable solid tumors due to exquisite chemosensitivity, mortality for patients with GCT comprises the most life years lost for non-pediatric malignancies. Given limited options for patients with platinum-resistant disease, improved insight into GCT biology could identify novel therapeutic options for patients with platinum-resistant disease. Recent studies into molecular characteristics of both early stage and advanced germ cell tumors suggest a role for rationally targeted agents and potentially immunotherapy. Recent developments: Recent GWAS meta-analyses have uncovered additional susceptibility loci for GCT and provide further evidence that GCT risk is polygenic. Chromosome arm level amplifications and reciprocal loss of heterozygosity have been described as significantly enriched in GCT compared to other cancer types. Contemporary analyses confirm ubiquitous gain of isochromosome 12 and mutations in addition to previously described GCT-associated genes such as KIT and KRAS. Alterations within the TP53-MDM2 signal transduction pathway appear to be enriched among patients with platinum-resistant disease. Potentially actionable targets, including alterations in TP53-MDM2, Wnt/β-catenin, PI3K, and MAPK signaling, are present in significant proportions of patients with platinum-resistant disease and may be exploited as therapeutic options. Pre-clinical and early clinical data also suggest a potential role for immunotherapy among patients with GCTs. Conclusion: Molecular characterization of GCT patients may provide biologic rationale for novel treatment options in patients with platinum-resistant disease.