Genetic control of susceptibility of testicular cancer

描述（由申请人提供）：睾丸生殖细胞肿瘤（TGCT）是影响年轻男性的最常见癌症，并且在过去50年中发病率急剧增加。易感性的遗传控制异常复杂，除了一个例外，控制易感性的遗传变异在人类中未被发现。我们在小鼠模型中发现了三种调节易感性的遗传修饰剂。增加易感性的Deadend 1 *Ter与参与RNA编辑的基因有关，并阻止特定miRNA与其靶mRNA的接触。同样，我们发现，部分缺陷的Eif 2s 2翻译起始因子在agouti-yellow位点抑制易感性。最后，我们发现，跨膜但不是可溶性亚型的试剂盒配体的损失增加小鼠的易感性。最近的两篇论文表明，Kit配体是人类TCGT的主要易感基因。总之，这些结果表明，靶mRNA中5 '帽和3' UTR之间的相互作用调节全局和可能的转录特异性翻译。TGCT干细胞似乎对翻译速率的变化异常敏感。有了这些重要的发现，TGCT修饰基因涉及相关的功能，我们现在可以解决有关发育重要的干细胞谱系-原始生殖细胞的肿瘤发生机制的具体问题。此外，我们发现在几个TGCT敏感株的自发转移。TGCT转移在人类中频繁发生，其机制知之甚少。因此，我们令人兴奋的发现使以前不可能的TGCT转移机制的独特研究成为可能。 我们提出了具体的目标来解决四个问题：（1）Eif 2s 2单倍性的TGCT抑制效应的机制是什么？ (2)Dnd 1突变体会影响RNA编辑吗？ (3)RNA编辑突变体影响TGCT易感性吗？ (4)在小鼠模型中，假定的TGCT转移的特征是什么？ 公共卫生相关性：睾丸癌是影响年轻男性的最常见恶性肿瘤之一。尽管易感性的遗传控制异常强大，但在发现这些可用于定义易感性机制并可作为诊断标志物或治疗靶点的基因方面几乎没有取得进展。我们发现了三个TGCT易感基因，其中两个表明mRNA翻译的控制对易感性有显着影响。在这个应用中，我们提出的研究，以测试机制的变化，翻译控制调节TGCT易感性的假设。我们还发现，并建议在我们的几个小鼠模型中表征自发性TGCT转移。

DESCRIPTION (provided by applicant): Testicular germ cell tumors (TGCTs) are the most common cancer affecting young men, and the incidence has increased dramatically in the last 50 years. The genetic control of susceptibility is unusually complex, and with a single exception genetic variants that control susceptibility elude discovery in humans. We discovered the identity of three genetic modifiers that modulate susceptibility in a mouse model. Deadend1*Ter, which increases susceptibility, is related to genes involved in RNA editing and blocks access of specific miRNAs to their target mRNAs. Similarly, we showed that partial deficiency for the Eif2s2 translation initiation factor at the agouti-yellow locus suppresses susceptibility. Finally, we showed that loss of the transmembrane but not the soluble isoform of the Kit ligand increases susceptibility in mice. Two recent papers showed that Kit ligand is a major TCGT susceptibility gene in humans. Together these results suggest that interactions between 5'cap and 3'UTR in target mRNAs modulate global and perhaps transcript-specific translation. TGCT stem cells appear to be unusually sensitive to changes in translation rates. With these important discoveries that TGCT modifier genes involve related functions, we can now address specific questions about mechanisms of tumorigenesis for a developmentally important stem cell lineage - primordial germ cells. In addition, we found spontaneous metastasis in several TGCT susceptible strains. TGCT metastasis occurs frequently in humans and the mechanisms are poorly understood. Our exciting discovery therefore enables unique studies of the mechanisms of TGCT metastasis that were not previously possible. We propose Specific Aims to address four questions: (1) What are the mechanisms for TGCT suppressor effects of Eif2s2 haplosufficiency? (2) Do Dnd1 mutants affect RNA editing? (3) Do RNA editing mutants affect TGCT susceptibility? (4) What are the characteristics of putative TGCT metastases in mouse models? PUBLIC HEALTH RELEVANCE: Testicular cancer is one of the most common malignancies affecting young men. Although the genetic control of susceptibility is unusually strong, little progress has been made finding these genes that could be used define the mechanisms of susceptibility and that could serve as diagnostic markers or as treatment targets. We discovered three TGCT susceptibility genes, two of which suggest that control of mRNA translation has dramatic effects on susceptibility. In this application, we propose studies to test hypotheses about mechanisms by which changes in translation control modulate TGCT susceptibility. We also discovered, and propose to characterize spontaneous TGCT metastases in several of our mouse models.