Genetic control of susceptibility of testicular cancer

睾丸癌易感性的基因控制

基本信息

批准号：
8433991
负责人：
JOSEPH H. NADEAU
金额：
$ 52.72万
依托单位：
PACIFIC NORTHWEST RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-06-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8433991
关键词：
129/Sv Mouse 3&apos Untranslated Regions Accounting Address Affect Apolipoproteins B Apoptosis Bilateral Biological Assay Biology Cell Culture Techniques Cell Lineage Cellular biology Characteristics Child Childhood Testicular Germ Cell Tumor Complex Development Diagnostic Disease susceptibility Enterochromaffin Cells Environmental Risk Factor Family Fetal Development Frequencies Funding Future Gene Mutation Generations Genes Genetic Genetic Epistasis Genetic Risk Genetic Translation Goals Heterozygote Human In Vitro Inbred Strain Incidence Infertility Location Malignant Childhood Neoplasm Malignant Neoplasms Malignant neoplasm of testis Mammals Messenger RNA MicroRNAs Modeling Molecular Mus Mutant Strains Mice Mutation Nature Neoplasm Metastasis Nephroblastoma Paper Parents Pathway interactions Peptide Initiation Factors Population Attributable Risks Predisposition Process Process Measure Protein Isoforms Proteins Publishing RNA Editing Reporting Resistance Risk Factors Role Signal Transduction Site Son Specificity Steel Stem Cell Factor Stem cells Structure of primordial sex cell Susceptibility Gene Testicular Germ Cell Tumor Testing Therapeutic Intervention Transcript Translations Tumor Stem Cells Tumor Suppressor Proteins Urogenital Abnormalities Validation Variant Wild Type Mouse Y Chromosome base cell motility congenic early childhood gene interaction genetic variant in vivo lymph nodes male mouse model mutant novel public health relevance research study tumor tumorigenesis young man

项目摘要

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?

描述（由申请人提供）：睾丸生殖细胞肿瘤（TGCT）是影响年轻人的最常见癌症，在过去的50年中，发生率显着增加。易感性的遗传控制异常复杂，并且有一个单一的例外遗传变异，可以控制人类中的敏感性。我们发现了在小鼠模型中调节敏感性的三个遗传修饰符的身份。 DeadEnd1*提高敏感性，与参与RNA编辑的基因有关，并阻止特定的miRNA进入其靶mRNA。同样，我们表明在Agouti-Yello基因座处的EIF2S2翻译起始因子的部分缺陷抑制了敏感性。最后，我们表明了跨膜的损失，但试剂配体的可溶同工型不会增加小鼠的敏感性。最近的两篇论文表明，KIT配体是人类中主要的TCGT敏感性基因。这些结果共同表明，目标mRNA中的5'CAP和3'UTR之间的相互作用调节全局，也许是转录本特定的翻译。 TGCT干细胞似乎对翻译速率的变化异常敏感。通过这些重要的发现，TGCT修饰基因涉及相关功能，我们现在可以解决有关肿瘤发生机制的特定问题，用于发育重要的干细胞谱系 - 原始生殖细胞。此外，我们在几个TGCT易感性菌株中发现了自发转移。 TGCT转移经常发生在人类中，而机制也很少理解。因此，我们令人兴奋的发现可以对以前无法实现的TGCT转移机制进行独特的研究。我们提出的具体目的是解决四个问题：（1）eIF2S2单倍宽度的TGCT抑制作用效应的机制是什么？（2）DND1突变体会影响RNA编辑吗？（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转移的特征是什么？