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的癌症，在过去的50年里发病率急剧增加。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没有被发现。我们在小鼠模型中发现了三种调节易感性的基因修饰因子。增加易感性的Deadend1*Ter与参与RNA编辑的基因有关，并阻止特定mirna进入其靶mrna。同样地，我们发现在刺黄位点部分缺乏Eif2s2翻译起始因子抑制了易感性。最后，我们发现Kit配体的跨膜而非可溶性异构体的缺失会增加小鼠的易感性。最近的两篇论文表明Kit配体是人类主要的TCGT易感基因。综上所述，这些结果表明目标mrna中5'cap和3'UTR之间的相互作用调节了全局翻译，甚至可能是转录特异性翻译。TGCT干细胞似乎对翻译速率的变化异常敏感。随着这些TGCT修饰基因涉及相关功能的重要发现，我们现在可以解决关于肿瘤发生机制的具体问题，这些机制是针对发育重要的干细胞谱系-原始生殖细胞。此外，我们在一些TGCT敏感菌株中发现了自发转移。TGCT转移在人类中经常发生，但机制尚不清楚。因此，我们令人兴奋的发现使TGCT转移机制的独特研究成为可能，这在以前是不可能的。我们提出了具体的目标来解决四个问题：(1)Eif2s2单倍性的TGCT抑制作用的机制是什么？(2) Dnd1突变体是否影响RNA编辑？(3) RNA编辑突变体是否影响TGCT易感性？(4)小鼠模型中假定的TGCT转移有什么特点？

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.