Myc Oncogene Mutations and Polymorphisms in Cancer

描述（由申请人提供）：c-MYC基因是人类癌症中任何致癌基因最常见的突变位点之一。大约15%的癌症表现出c-MYC基因的扩增，大约25%的乳腺癌有类似的突变。100%的伯基特淋巴瘤（Burkitt’s lymphoma）以及相关的小鼠浆细胞瘤（plas浆细胞瘤）均发生c-MYC染色体易位。除了这些严重的重排外，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%的伯基特淋巴瘤和艾滋病相关淋巴瘤具有改变已经易位的c-MYC基因的蛋白质结构的突变。从一个非常不同的角度来看，易患各种癌症的遗传单核苷酸多态性（snp）经常被定位在c-MYC基因内或附近。除了这些明显的突变和多态性外，据估计，高达70%的癌症过度表达c-MYC，以响应各种信号通路（如Wnt）的中断。癌症领域面临的一个主要问题是这些突变和多态性如何靶向c-MYC及其下游细胞靶标来介导致癌转化、细胞周期进展或细胞凋亡。更广泛的兴趣是c-MYC基因本身是如何响应不同的致癌信号通路而受到调节的。该项目的具体目标是：目标1：表征伯基特淋巴瘤和艾滋病相关淋巴瘤中c-MYC蛋白中常见的错义突变。我们的假设是，这些突变聚集在增强致癌活性的位点，并显著改变c-MYC靶基因的谱。目的2：表征c-MYC的一个新的直接靶点，即nol5a基因的功能，该基因被伯基特淋巴瘤相关的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增强了c-MYC的功能。目标3：表征在染色体8q24上一个大区域上的snp的功能，这是一个巨大的区域（bbb20 Mb），仅包含一个功能基因，即c-MYC。我们的假设是，这些snp映射到控制特定组织中c-MYC基因表达的非常远端的调控元件，并依赖于特定的遗传等位基因，使个体易患（或保护）结肠癌、前列腺癌和乳腺癌。

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.