Genetic Control of Susceptibility to Testicular Cancer

描述（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，其发病率在全球范围内急剧上升。需要遗传风险的遗传标记来识别易感个体，以进行定期监测和早期治疗。许多TGCT在胎儿发育期间由原始生殖细胞（PGCs）产生。关于这种多能干细胞谱系的遗传学或生物学知之甚少。129家族的近交系是唯一的菌株，其中自发TGCT发生在一个可观的频率（5%）。几个单基因突变如Ter、Ay和SI在致敏129遗传背景上调节易感性。这些菌株和突变体是PGC发育和TGCT易感性的遗传和发育研究的基础。在先前的授权期间，我们表明（a）Ter，已知的最有效的TGCT修饰物，由Deadend基因中的突变引起，（B）Ay基因座处的TGCT抑制因子是Raly或Eif 2b 2，但不是agglutamine，并且MGF增强子位于120 kb间隔中，其中MGF是唯一的常规基因，以及（c）几个单一修饰物相互作用以调节TGCT易感性，包括在p53/+ SIJ/+双突变小鼠中显著降低的易感性。 我们提出四个具体目标： 具体目标1。Ay突变体中的TGCT抑制子和Kitl*SI小鼠中的增强子的身份是什么？ 具体目标2。TGCT易感性修饰基因之间相互作用的本质是什么？ 具体目标3。Y染色体是否影响TGCT的易感性？ 具体目标4。RNA编辑基因的突变会影响TGCT的易感性吗？ 我们发现最有效的TGCT修饰基因（Ter）可能涉及RNA编辑异常，这为探索这一显着但知之甚少的过程在干细胞生物学和TGCT易感性中的作用提供了令人兴奋的新机会。

DESCRIPTION (provided by applicant): Testicular germ cells tumors (TGCTs) are the most common cancer affecting young men and their incidence has been rising dramatically world-wide. Genetic markers for inherited risk are needed to identify susceptible individuals for regular surveillance and early treatment. Many TGCTs arise from primordial germ cells (PGCs) during fetal development. Little is known about the genetics or biology of this pluripotent stem cell lineage. The 129 family of inbred strains are the only strains in which spontaneous TGCTs occur at an appreciable frequency (5%). Several single gene mutations such as Ter, Ay and SI modulate susceptibility on the sensitized 129 genetic background. These strains and mutants are the foundation for genetic and developmental studies of PGC development and TGCT susceptibility. During the previous grant period, we showed that (a) Ter, the most potent TGCT modifier known, results from a mutation in the Deadend gene, (b) the TGCT suppressor at the Ay locus is Raly or Eif2b2 but not agouti, and also that the MGF enhancer is located in a 120 kb interval in which MGF is the only conventional gene, and (c) several single modifiers interact to modulate TGCT susceptibility, including dramatically reduced susceptibility in p53/+ SIJ/+ double mutant mice. We propose four Specific Aims: Specific Aim 1. What is the identity of the TGCT suppressor in Ay mutants and the enhancer in Kitl*SI mice? Specific Aim 2. What is the nature of the interactions between TGCT susceptibility modifier genes? Specific Aim 3. Does the Y chromosome affect TGCT susceptibility? Specific Aim 4. Do mutations in RNA editing genes affect TGCT susceptibility? Our discovery that the most potent TGCT modifier gene (Ter) probably involves anomalies in RNA editing raises exciting new opportunities to explore the role of this remarkable but poorly understood process in stem cell biology and TGCT susceptibility.