Genetic Control of Susceptibility to Testicular Cancer

睾丸癌易感性的基因控制

• 批准号: 7254184
• 负责人: JOSEPH H. NADEAU
• 金额: $ 45.34万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7254184
• 关键词: Adenosine; Affect; Binding; Biology; Cell Lineage; Cellular biology; Child; Childhood; Childhood Testicular Germ Cell Tumor; Complementary DNA; Complex; Cytidine; Cytidine Deaminase; Development; Early treatment; Enhancers; Environmental Risk Factor; Enzymes; Family; Fetal Development; Foundations; Frequencies; Gene Mutation; Genes; Genetic; Genetic Complementation Test; Genetic Markers; Genetic Predisposition to Disease; Gonadal Dysgenesis; Grant; Human; Inbred Strain; Inbred Strains Mice; Incidence; Individual; Infertility; Inherited; Inosine; KITLG gene; Lead; Malignant Neoplasms; Malignant neoplasm of testis; Measures; Medical Surveillance; Membrane; Molecular; Molecular Analysis; Mus; Mutant Strains Mice; Mutation; Nature; Nonsense Mutation; Pluripotent Stem Cells; Predisposition; Process; RNA; RNA Editing; Rate; Risk; Risk Factors; Role; Sequence Analysis; Stem cells; Structure of primordial sex cell; TP53 gene; Testicular Germ Cell Tumor; Testing; Transgenic Mice; Tumor Suppressor Proteins; Uridine; Y Chromosome; base; congenic; developmental genetics; dsRNA adenosine deaminase; loss of function; male; men; mutant; sex; tumor; tumorigenesis

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.

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的癌症，其发病率在世界范围内急剧上升。需要遗传风险的遗传标记来确定易感个体，以便进行定期监测和早期治疗。在胎儿发育过程中，许多tgct起源于原始生殖细胞（PGCs）。人们对这种多能干细胞谱系的遗传学和生物学知之甚少。129家族的近交系是唯一出现自发性TGCTs的菌株，频率相当高（5%）。一些单基因突变，如Ter， Ay和SI在致敏129遗传背景下调节易感性。这些菌株和突变体是PGC发育和TGCT易感性遗传和发育研究的基础。前面的格兰特时期,我们表明,(a) Ter,最有力TGCT修饰符,结果无出路的一个突变基因,(b)的TGCT抑制Ay轨迹日或Eif2b2但不是刺,而且MGF增强器位于一个120 kb的间隔MGF是唯一的传统基因,和(c)几个单一修饰符交互调节TGCT易感性,包括显著的敏感性降低p53 / + SIJ / +突变小鼠的两倍。