Primary Mediastinal and Testicular Germ Cell Tumors in Adolescents and Adults: A Comparison of Genomic Alterations and Clinical Implications

SIMPLE SUMMARY: The germ cell tumors (GCTs) family is a heterogeneous group of neoplasms that includes tumors affecting testis (TGCTs) and rarer cases occurring in extragonadal sites. Mediastinal germ cell tumors (MGCTs) are more aggressive and have poorer prognosis. Due to their rarity of MGCTs, few molecular and clinical studies are reported. MGCTs share biological similarities with TGCT, and international guidelines recommend use of the same therapies validated for TGCT. However, while high response rate is achieved in TGCT, MGCT tend to be resistant to therapy. This review resumes all molecular findings reported in MGCTs, summarizing molecular characteristics common with TGCT and highlighting the different molecular alterations that characterize mediastinal tumors. A deeper understanding of the MGCT biology will help in clinical management of these patients. ABSTRACT: Mediastinal germ cell tumors (MGCTs) share histologic, molecular and biomarkers features with testicular GCTs; however, nonseminomatous MGCTs are usually more aggressive and have poorer prognosis than nonseminomatous TGCTs. Most nonseminomatous MGCT cases show early resistance to platinum-based therapies and seldom have been associated with the onset of one or more concomitant somatic malignancies, in particular myeloid neoplasms with recent findings supporting a common, shared genetic precursor with the primary MGCT. Genomic, transcriptomic and epigenetic features of testicular GCTs have been extensively studied, allowing for the understanding of GCT development and transformation of seminomatous and nonseminomatous histologies. However, MGCTs are still lacking proper multi-omics analysis and only few data are reported in the literature. Understanding of the mechanism involved in the development, in the progression and in their higher resistance to common therapies is still poorly understood. With this review, we aim to collect all molecular findings reported in this rare disease, resuming the similarities and disparities with the gonadal counterparts.