Between a Rock and a Hard Place: An Epigenetic-Centric View of Testicular Germ Cell Tumors

Abstract

Compared to many common solid tumors, the main genetic drivers of most testicular germ cell tumors (TGCTs) are unknown. Decades of focus on genomic alterations in TGCTs including awareness of a near universal increase in copies of chromosome 12p have failed to uncover exceptional driver genes, especially in genes that can be targeted therapeutically. Thus far, TGCT patients have missed out on the benefits of targeted therapies available to treat most other malignancies. In the past decade there has been a greater appreciation that epigenetics may play an especially prominent role in TGCT etiology, progression, and hypersensitivity to conventional chemotherapy. While genetics undoubtedly plays a role in TGCT biology, this mini-review will focus on the epigenetic "states" or features of testicular cancer, with an emphasis on DNA methylation, histone modifications, and miRNAs associated with TGCT susceptibility, initiation, progression, and response to chemotherapy. In addition, we comment on the current status of epigenetic-based therapy and epigenetic biomarker development for TGCTs. Finally, we suggest a unifying "rock and a hard place" or "differentiate or die" model where the tumorigenicity and curability of TGCTs are both dependent on common but still ill-defined epigenetic states.

Keywords: DNA methylation; cisplatin; embryonal carcinoma; epigenetics; resistance; testicular cancer; testicular germ cell tumors.

Figure 1

An epigenetic-centric view of testicular germ cell tumors (TGCT) etiology. While genetics undoubtedly play a role in TGCT development, epigenetic altering factors in the microenvironment of the testis from both internal and external sources may be a more important driving factor. The model also suggests that even inherited genetic germline variants and somatic cancer alterations may participate in establishing tumorigenic epigenetic state(s) of TGCTs. DSD, disorders of sex development, TDS, testicular dysgenesis syndrome.

Figure 2

Rock and a hard place model of TGCT chemosensitivity. The model speculates that an explanation for why TGCTs are so sensitive to cisplatin-based therapy compared to other solid tumors is that the very epigenetic state(s) that drives tumorigenicity are the same or “linked” to the epigenetic state(s) that drive chemosensitivity. In such a model there are two main outcomes for cisplatin treated TGCTs; to either die or differentiate (in the extreme case to benign teratoma). This situation is predicted not to occur in other solid tumor types, or their cancer stem cells. In rare cases the epigenetic state driving tumorigenicity of TGCTs becomes uncoupled from the epigenetic state driving chemosensitivity resulting in cisplatin resistant TGCTs that retain tumorigenicity. Epigenetic drugs have the potential to “recouple” chemosensitivity with tumorigenicity or to target unique epigenetic vulnerabilities of TGCTs directly. Epigenetic drugs that cause teratoma formation would not be optimal as teratoma is still a clinical issue necessitating surgical removal.