文章：

睾丸生殖细胞肿瘤：易感基因与男性生殖细胞生态位

Testicular germ cell tumours: predisposition genes and the male germ cell niche

原文发布日期：2011-03-17

DOI: 10.1038/nrc3021

类型: Review Article

开放获取: 否

要点：

1. Testicular germ cell tumours (TGCTs) are the most frequent solid cancer in young adult Caucasian men; they have shown an increased incidence over the past four decades and are putatively derived from primordial germ cells (PGCs) or gonocytes.
2. Genome-wide association studies (GWAS) have revealed loci that suggest predisposition genes that are central to normal PGC biology (KIT ligand (KITLG; also known as SCF), sprouty 4 (SPRY4), BCL-2-antagonist/killer 1 (BAK1), telomerase reverse transcriptase (TERT), activating transcription factor 7 interacting protein (ATF7IP) and doublesex and mab-3-related transcription factor 1 (DMRT1)).
3. KITLG, SPRY4 and BAK1 are involved in KIT signalling, which is crucial to PGC migration and survival and is an important pathway that is frequently activated in TGCTs that occur in older men.
4. TERT and ATF7IP maintain telomere length and are reactivated in a range of tumour types.
5. DMRT1 is responsible for male sex determination. Experimental loss leads to TGCTs in mouse models and genomic gain and overexpression is seen in the spermatocytic seminoma subtype of TGCTs.
6. Spermatocytic seminomas exhibit overexpression and mutations of fibroblast growth factor 3 (FGFR3) and HRAS. These mutations confer a selective advantage to the spermatogonial stem cells within the testes and accrue over time, linking ageing to cancer predisposition and congenital syndromes in the offspring of affected gametes.
7. This improved understanding of TGCT predisposition and biology will lead to further refinements in the clinical management of this disease.

要点翻译：

1. 睾丸生殖细胞肿瘤（TGCTs）是高加索裔年轻男性中最常见的实体癌；过去四十年来其发病率持续上升，这类肿瘤推测源自原始生殖细胞（PGCs）或性原细胞。
2. 全基因组关联研究（GWAS）已发现的基因位点表明，易感基因在正常原始生殖细胞生物学中起核心作用（包括KIT配体（KITLG，亦称SCF）、sprouty 4（SPRY4）、BCL-2拮抗剂/杀伤因子1（BAK1）、端粒酶逆转录酶（TERT）、激活转录因子7相互作用蛋白（ATF7IP）以及doublesex和mab-3相关转录因子1（DMRT1））。
3. KITLG、SPRY4和BAK1参与KIT信号传导，该通路不仅对原始生殖细胞的迁移和存活至关重要，也是老年男性TGCT患者中频繁激活的重要通路。
4. TERT和ATF7IP负责维持端粒长度，并在多种肿瘤类型中被重新激活。
5. DMRT1主导男性性别决定。实验性缺失该基因会导致小鼠模型发生TGCT，而在TGCT的精母细胞瘤亚型中观察到该基因的基因组扩增和过度表达。
6. 精母细胞瘤显示成纤维细胞生长因子受体3（FGFR3）和HRAS的过度表达与突变。这些突变赋予睾丸内精原干细胞选择性优势，并随时间累积，从而将衰老与癌症易感性及受影响配子后代的先天性综合征联系起来。
7. 对TGCT易感性和生物学特征的深入理解，将推动该疾病临床治疗策略的进一步完善。

英文摘要：

Testicular germ cell tumours (TGCTs) of adults and adolescents are putatively derived from primordial germ cells or gonocytes. Recently reported genome-wide association studies implicate six gene loci that predispose to TGCT development. Remarkably, the functions of proteins encoded by genes within these regions bridge our understanding between the pathways involved in primordial germ cell physiology, male germ cell development and the molecular pathology of TGCTs. Furthermore, this improved understanding of the mechanisms underlying TGCT development and dissemination has clinical relevance for the management of patients with these tumours.

摘要翻译： 

成人及青少年睾丸生殖细胞肿瘤（TGCTs）据认为起源于原始生殖细胞或生殖母细胞。近期发表的基因组关联研究鉴定出6个易感基因位点与TGCT发生相关。值得注意的是，这些区域内基因编码蛋白的功能，将原始生殖细胞生理、男性生殖细胞发育与TGCT分子病理之间的通路联系了起来。此外，对TGCT发生和播散机制的深入理解，也为这些肿瘤患者的临床管理提供了相关依据。

原文链接：

Testicular germ cell tumours: predisposition genes and the male germ cell niche