Singh Ratnakar, Fazal Zeeshan, Freemantle Sarah J, Spinella Michael J
Department of Comparative Biosciences and the Carle Illinois College of Medicine and the Cancer Center of Illinois, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Cancers (Basel). 2021 Mar 25;13(7):1506. doi: 10.3390/cancers13071506.
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.
与许多常见实体瘤相比，大多数睾丸生殖细胞肿瘤（TGCT）的主要遗传驱动因素尚不清楚。数十年来，对TGCT基因组改变的关注，包括对12号染色体短臂拷贝数几乎普遍增加的认识，都未能发现异常的驱动基因，尤其是那些可用于靶向治疗的基因。到目前为止，TGCT患者错过了大多数其他恶性肿瘤可用的靶向治疗带来的益处。在过去十年中，人们越来越认识到表观遗传学可能在TGCT的病因、进展以及对传统化疗的超敏反应中发挥特别突出的作用。虽然遗传学无疑在TGCT生物学中发挥作用，但本综述将重点关注睾丸癌的表观遗传“状态”或特征，重点是与TGCT易感性、起始、进展和化疗反应相关的DNA甲基化、组蛋白修饰和微小RNA。此外，我们对基于表观遗传学的TGCT治疗和表观遗传生物标志物开发的现状进行了评论。最后，我们提出了一个统一的“进退两难”或“分化或死亡”模型，其中TGCT的致瘤性和可治愈性都取决于常见但仍未明确的表观遗传状态。
