Genomic Features for Therapeutic Insights of Chemotherapy-Resistant, Primary Mediastinal Nonseminomatous Germ Cell Tumors and Comparison with Gonadal Counterpart

Abstract

Primary mediastinal nonseminomatous germ cell tumors (PMNSGCT) frequently become refractory to chemotherapy, and no effective salvage therapy exists. We performed genomic profiling on a series of 44 PMNSGCT and compared the results with those from chemorefractory, metastatic pure seminomatous (Sem, n = 22) and nonseminomatous (NS, n = 86) testicular germ cell tumors. Archival tissues were sequenced by a hybrid capture-based technology (FoundationONE; Foundation Medicine, Inc., Cambridge, MA). Microsatellite instability (MSI) and tumor mutational burden (TMB, mutations [mut]/Mb) were determined.Statistically significant differences in genomic alterations (GA) of PMNSGCT versus NS included higher TP53 pathway GA (p < .0001), PIK3CA pathway GA (p < .0001), and lower cell-cycle pathway GA (p = .0004). There were no MSI-high PMNSGCT cases. Mean TMB was similar between the groups, but there were more ≥10 mut/Mb in the PMNSGCT group versus NS (11.4% vs. 4.6%).The GA identified in PMNSGCT were similar to the findings from NS, with differential opportunities for targeted therapies and immunotherapies. Further study of precision treatments appears warranted.

Figure 1.

Oncoprint displaying all the genomic alterations observed in the population of 44 patients with primary mediastinal nonseminomatous germ cell tumors. Genes are ordered alphabetically. At the top of the figure, the plot of tumor mutational burden (mutations/Mb) for each single patient is reported. On the right, there is a plot indicating, for each single gene, the frequency of observed genomic alterations. Abbreviation: GCT, germ cell tumor.