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.

Reciprocal epigenetic remodeling controls testicular cancer hypersensitivity to hypomethylating agents and chemotherapy

“…This hypersensitivity is on the order of 100-to 1000-fold compared to the sensitivity of other solid cancers, extends to cisplatinresistant TGCT cells, and depends on very high levels of the DNA methyltransferase, DNMT3B. These findings are in line with the hypothesis that due to their germ cell origins and low mutational burden, TGCTs may be especially driven and sustained by distinct epigenetic alterations resulting in distinct vulnerabilities to epigenetic drugs [9][10][11]. Importantly, hypomethylating agents have been shown to resensitize cisplatinresistant cells to cisplatin and we and a second group have provided early phase clinical findings suggesting that a subset of cisplatin refractory TGCT patients favorably respond to guadecitabine in combination with cisplatin [4][5][6][7][12][13][14].…”

“…Although there are no effective alternative or targeted therapies available for cisplatin refractory TGCT patients, recent preclinical and early clinical trial data suggest a subset of cisplatin refractory TGCTs may be hypersensitive to DNA hypomethylating agents [4][5][6][7][8][12][13][14]. The mechanisms accounting for the hypersensitivity of TGCT cells to hypomethylating agents are entirely unknown apart from a reported dependence on high-level expression of DNMT3B [6][7][8][9]. Very few studies have addressed the issue of resistance to hypomethylating agents, and these are mainly centered on acute myeloid leukemia [27,28].…”

Therapeutical interference with the epigenetic landscape of germ cell tumors: a comparative drug study and new mechanistical insights

“…hypomethylation in SE and hypermethylation in non-seminomas [ 8 , 10 ]. Little is known about histone modifications in GCT, but a few studies and review articles point out that GCTs in general may have high levels of bivalent histone marks H3K27me3 and H3K4me3 [ 11 , 12 ]. Almstrup et al detected high levels of H3K9me2, H3K27me3 and H3K4me1 and low levels of H3K4me2/3 in SE, and vice versa in EC [ 13 ].…”

To Be or Not to Be a Germ Cell: The Extragonadal Germ Cell Tumor Paradigm

“…In the present work, we critically review old and new evidence that the unique pluripotency status is imposed on hPGCs by epigenetics traits regulated by pluripotency, and germline transcription factors that make these cells prone to undergo tumorigenesis. Such notion is discussed under the view that PGCs might be part of a pluripotent stem/progenitor cell pool exhibiting common markers that contribute to various somatic cell lineages (see also [ 1 , 2 , 3 ]).…”