Myc Oncogene Mutations and Polymorphisms in Cancer

癌症中的 Myc 癌基因突变和多态性

• 批准号: 7995269
• 负责人: MICHAEL David COLE
• 金额: $ 33.68万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7995269
• 关键词: 8q24; AIDS-Related Burkitt' s Lymphoma; Alleles; Apoptosis; Biogenesis; Burkitt Lymphoma; Cancer Cell Growth; Cell Cycle Progression; Chromosomal translocation; Chromosomes; Colon Carcinoma; DNA Sequence Rearrangement; Distal; Exhibits; Gene Expression; Gene Targeting; Genes; Genetic Polymorphism; Goals; Growth; Human; Human Genome; Individual; Inherited; MYC Family Protein; MYC gene; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Mediating; Missense Mutation; Mus; Mutate; Mutation; Oncogenes; Oncogenic; Plasmacytoma; Play; Proteins; Regulatory Element; Ribosomes; Role; Signal Pathway; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Site; Tissues; Variant; c-myc Genes; cancer risk; cellular targeting; interest; malignant breast neoplasm; novel; overexpression; protein structure; public health relevance; response

DESCRIPTION (provided by applicant): The c-MYC gene is among the most frequent sites of mutation for any oncogene in human cancer. Approximately 15% of all cancers exhibit amplification of the c-MYC gene and about 25% of breast cancers have similar mutations. Chromosomal translocations at c-MYC occur in 100% of Burkitt's lymphomas, as well as in the related mouse plasmacytomas. In addition to these gross rearrangements, missense mutations can also play a major role in the oncogenic activity of c-MYC, and more than 60% of Burkitt's and AIDS-associated lymphomas have mutations that alter the protein structure of the already translocated c-MYC gene. From a very different perspective, inherited Single Nucleotide Polymorphisms (SNPs) that predispose to various cancers have frequently been mapped within or near the c-MYC gene. Beyond these overt mutations and polymorphisms, it is estimated that up to 70% of all cancers overexpress c-MYC in response to disruptions in various signaling pathways such as Wnt. A major question confronting the cancer field is how these mutations and polymorphisms target c-MYC and its downstream cellular targets to mediate oncogenic transformation, cell cycle progression or apoptosis. Of broader interest is how the c-MYC gene itself is regulated in response to diverse oncogenic signaling pathways. The specific goals of this project are to: Aim 1: Characterize the missense mutations frequently found in the c-MYC protein in Burkitt's and AIDS-associated lymphomas. Our hypothesis is that these mutations cluster at sites that enhance oncogenic activity and dramatically shift the profiles of c-MYC target genes. Aim 2: Characterize the function of a novel direct target of c-MYC, the nol5a gene, that is hyperactivated by Burkitt's lymphoma associated c-MYC mutations. Our hypothesis is that the Nol5a protein potentiates c-MYC function through its role in ribosome biogenesis. Aim 3: Characterize the function of SNPs that map over a large domain on chromosome 8q24, a huge region (>2 Mb) that harbors only a single functional gene, i.e. c-MYC. Our hypothesis is that these SNPs map to very distal regulatory elements that control c-MYC gene expression in specific tissues and predispose (or protect) individuals from colon, prostate and breast cancer, dependent on the particular inherited allele. PUBLIC HEALTH RELEVANCE: Certain cellular genes are frequently mutated or misregulated to cause the abnormal growth of cancer cells. One of the most commonly mutated genes is called c-myc, and this gene is known to be an important regulatory of growth. The goal of the project is to understand how mutations change c-myc function in some cancers and how inherited variations near c-myc in the human genome can increase the risk of cancer.

描述(由申请人提供)：c-myc基因是人类癌症中最常见的癌基因突变位点之一。大约15%的癌症表现出c-myc基因的扩增，大约25%的乳腺癌具有类似的突变。C-myc的染色体易位发生在100%的Burkitt淋巴瘤以及相关的小鼠浆细胞瘤中。除了这些大的重排，错义突变也可以在c-myc的致癌活性中发挥主要作用，超过60%的Burkitt‘s和AIDS相关淋巴瘤的突变会改变已经易位的c-myc基因的蛋白质结构。从一个非常不同的角度来看，易患各种癌症的遗传性单核苷酸多态(SNPs)经常被定位在c-myc基因内部或附近。除了这些明显的突变和多态之外，据估计，高达70%的所有癌症都过度表达c-myc，以应对各种信号通路的中断，如Wnt。癌症领域面临的一个主要问题是，这些突变和多态如何靶向c-myc及其下游细胞靶点，以介导致癌转化、细胞周期进展或细胞凋亡。更令人感兴趣的是c-myc基因本身是如何在不同的致癌信号通路中被调节的。该项目的具体目标是：目标1：鉴定在Burkitt‘s和AIDS相关淋巴瘤中经常发现的c-myc蛋白的错义突变。我们的假设是，这些突变聚集在增强致癌活性的位置，并极大地改变了c-myc靶基因的图谱。目的：研究一个新的c-myc直接靶点nol5a基因的功能，该基因被Burkitt淋巴瘤相关的c-myc突变过度激活。我们的假设是，NOL5a蛋白通过其在核糖体生物发生中的作用而增强c-myc的功能。目的3：研究位于染色体8q24上一个大区域的SNPs的功能，该区域(&gt；2Mb)只含有一个功能基因，即c-myc。我们的假设是，这些SNPs映射到非常远端的调控元件，这些调控元件控制着c-myc基因在特定组织中的表达，并根据特定的遗传等位基因易患(或保护)个人患结肠癌、前列腺癌和乳腺癌。 与公共卫生相关：某些细胞基因经常发生突变或调控不当，从而导致癌细胞的异常生长。最常见的突变基因之一是c-myc，该基因被认为是一种重要的生长调节基因。该项目的目标是了解突变如何改变某些癌症中的c-myc功能，以及人类基因组中c-myc附近的遗传变异如何增加癌症风险。