Myc Oncogene Mutations and Polymorphisms in Cancer

癌症中的 Myc 癌基因突变和多态性

• 批准号: 7783140
• 负责人: MICHAEL David COLE
• 金额: $ 34.72万
• 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/7783140
• 关键词: 8q24; AIDS-Related Burkitt' s Lymphoma; Alleles; Apoptosis; Biogenesis; Burkitt Lymphoma; Cancer Cell Growth; Cell Cycle Progression; Chromosomal translocation; Chromosomes; Colon; 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; Maps; Mediating; Missense Mutation; Mus; Mutate; Mutation; Oncogenes; Oncogenic; Plasmacytoma; Play; Prostate; 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基因是人类癌症中任何癌基因最常见的突变部位之一。大约15％的癌症表现出C-MYC基因的扩增，约25％的乳腺癌具有相似的突变。 C-MYC处的染色体易位发生在伯基特淋巴瘤的100％以及相关的小鼠浆细胞瘤中。除了这些严重的重排外，错义突变还可以在C-MYC的致癌活性中起主要作用，并且超过60％的Burkitt和与AIDS相关的淋巴瘤具有突变，可以改变已经转移的C-Myc基因的蛋白质结构。从截然不同的角度来看，遗传的单核苷酸多态性（SNP）经常在C-MYC基因内部或附近映射到各种癌症。除了这些明显的突变和多态性外，据估计，所有癌症中有70％过表达C-MYC，响应各种信号传导途径（例如Wnt）的破坏。癌症领域面临的一个主要问题是这些突变和多态性如何针对C-MYC及其下游细胞靶标介导致癌转化，细胞周期进程或凋亡。更广泛的关注是如何根据各种致癌信号通路来调节C-MYC基因本身。该项目的具体目标是：目标1：表征伯基特（Burkitt）和艾滋病相关淋巴瘤中C-MYC蛋白中经常发现的错义突变。我们的假设是，这些突变聚类在增强致癌活性并大大改变C-MYC靶基因的谱的位点。 AIM 2：表征NOL5A基因C-MYC新型直接靶标的功能，该靶标由Burkitt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增强了C-MYC的功能。 AIM 3：表征SNP的功能，该功能在8q24染色体上的大域上映射，这是一个仅包含单个功能基因的巨大区域（> 2 MB），即C-MYC。我们的假设是，这些SNP映射到非常远端调节元件，这些元件控制特定组织中C-MYC基因的表达，并倾向于（或保护）个体免受结肠，前列腺和乳腺癌的侵害，取决于特定的遗传等位基因。 公共卫生相关性：某些细胞基因经常被突变或误导，以引起癌细胞异常的生长。最常见的突变基因之一称为C-MYC，该基因被称为生长的重要调节。该项目的目的是了解突变如何在某些癌症中改变C-MYC功能，以及人类基因组中C-MYC附近的遗传变化如何增加癌症的风险。