Van Der Zwan Yvonne G, Stoop Hans, Rossello Fernando, White Stefan J, Looijenga Leendert H J
Department of Pathology, Erasmus MC- University Medical Center Rotterdam, Josephine Nefkens Institute, Rotterdam, The Netherlands.
Int J Dev Biol. 2013;57(2-4):299-308. doi: 10.1387/ijdb.130017ll.
Embryonic development is strictly controlled by functionality of genes in which the existing networks can act both on transcription and translation regulation. Germ cell cancers (GCC) are unique because of a number of characteristics. In spite of their clinical presentation, i.e., predominantly after puberty, they arise from primordial germ cells/gonocytes that have failed appropriate maturation to either pre-spermatogonia or oogonia. GCC mimic embryonal development to a certain extent, including capacity for totipotency. This knowledge has allowed the identification of informative diagnostic markers, including OCT3/4 (POU5F1), SOX2 and SOX17. An additional marker is the overall demethylated status of the genome. Genetic mutations in GCC are rare, which is exceptional for solid cancers. Our hypothesis is that a disturbed epigenetic regulation (through combined interaction of genetic or environmental parameters; referred to as genvironment) affect embryonic germ cell development, resulting in delayed or blocked maturation, and potentially progression to GCC. In this respect, studies of patients with Disorders of Sex Development (DSD) have increased our knowledge significantly. Genvironmental influences can lead to retention of existence of embryonic germ cells, the first step in the pathogenesis of GCC, resulting into the precursor lesions gonadoblastoma or carcinoma in situ. Identification of epigenetic alterations could lead to better understanding these processes and development of specific markers for early detection, eventually leading to development of targeted treatment. This review describes an interactive model related to the role of epigenetics in GCC pathogenesis, focusing on DNA methylation, histone modifications, epigenetic memory and inheritance, as well as environmental factors.
胚胎发育受到基因功能的严格控制，现有网络可作用于转录和翻译调控。生殖细胞癌（GCC）因其多种特征而独具特色。尽管其临床表现主要出现在青春期后，但它们起源于未能正常成熟为精原细胞前体细胞或卵原细胞的原始生殖细胞/生殖母细胞。GCC在一定程度上模拟胚胎发育，包括全能性。这一认识使得能够鉴定出有诊断价值的标志物，包括OCT3/4（POU5F1）、SOX2和SOX17。另一个标志物是基因组的整体去甲基化状态。GCC中的基因突变很少见，这在实体癌中是例外情况。我们的假设是，表观遗传调控紊乱（通过遗传或环境参数的联合相互作用；称为基因环境）影响胚胎生殖细胞发育，导致成熟延迟或受阻，并可能进展为GCC。在这方面，对性发育障碍（DSD）患者的研究显著增加了我们的认识。基因环境影响可导致胚胎生殖细胞持续存在，这是GCC发病机制的第一步，可导致前体病变性腺母细胞瘤或原位癌。鉴定表观遗传改变可能有助于更好地理解这些过程，并开发早期检测的特异性标志物，最终导致靶向治疗的发展。本综述描述了一个与表观遗传学在GCC发病机制中的作用相关的交互模型，重点关注DNA甲基化、组蛋白修饰、表观遗传记忆和遗传以及环境因素。
