Unveiling non-coding drivers of cancer

摘要 癌症是一种主要由DNA上的体细胞改变积累引起的疾病。这些变化可能会破坏 肿瘤抑制因子，激活癌基因，并创造具有新功能的新基因。许多改变和基因 可以作为诊断和预后的生物标志物，有些可以被药物靶向。高通量 测序技术使得能够快速发现导致疾病进展的基因， 药物反应在过去的几年里，基因组测序的速度呈爆炸式增长。的主要重点 癌症研究一直致力于检测点突变、拷贝数变化和蛋白质表达变化， 编码基因除了编码蛋白质的基因，还有成千上万的非编码RNA 人类基因组中的非编码RNA（ncRNA），人们对其了解较少。他们中的一些人被认为扮演着重要的角色 在正常的细胞过程中，有一小部分可以促进肿瘤的生长、转移和耐药性。 更重要的是，一些ncRNA具有临床意义，因为它们可以用作生物标志物和/或药物， 目标的然而，绝大多数ncRNA的功能及其对癌症的贡献是未知的。 仍然不清楚。在这项研究中，我们将进行全基因组筛选新的癌症驱动ncRNA， 利用来自几个国家和国际癌症基因组测序的现有大规模数据， 财团。在肿瘤组织中，ncRNA的正常功能可被不同类型的体细胞癌干扰。 改变，例如点突变、DNA拷贝改变、基因组重排、表观遗传改变等。 对这些不同类型的改变中的每一种的调查需要专门的分析方法。以识别 新的癌症驱动ncRNA，我们将特别关注一个研究较少的改变类型-基因组 重新安排它们包括缺失、重复、倒位、易位和其他更复杂的形式。 基因组重排的一个主要后果是它们可以改变基因组中的DNA含量。我们 假设肿瘤特异性体细胞基因组重排可以重组ncRNA， 肿瘤发生例如，我们将系统地筛选新的监管职能， ncRNA通过由于体细胞基因组重排而在基因组中重新定位调节元件。我们将 还筛选通过DNA片段改组产生的新的ncRNA种类，其携带新的功能， 有助于肿瘤发生。在进化上，外显子改组是形成新基因的重要机制， 基因.将实施多种互补战略，以克服各种科学和技术 挑战我们的研究可能会导致新的致癌ncRNA，新的生物标志物和潜在的发现。 药物靶点，并揭示了新的细胞过程在正常和疾病条件下的规定。

ABSTRACT Cancer is a disease mostly caused by accumulation of somatic alterations on DNA. These alterations can disrupt tumor suppressors, activate oncogenes, and create new genes with novel functions. Many alterations and genes can serve as biomarkers for diagnosis and prognosis, and some can be targeted by drugs. High-throughput sequencing technologies have enabled rapid discovery of genes which contribute to disease progression and drug response. The past few years have seen an explosion in the rate of genome sequencing. The main focus of cancer research has been on detecting point mutations, copy number changes and expression changes of protein- coding genes. In addition to the protein-coding genes, there are tens of thousands of non-coding RNAs (ncRNAs) in the human genome that are less well-understood. Some of them are known to play important roles in normal cellular processes, and a small subset can promote tumor growth, metastasis and drug resistance. More importantly, some ncRNAs are of clinical significance as they can be used as biomarkers and/or drug targets. However, the vast majority of ncRNAs have unknown functions and their contributions to cancer remain unclear. In this study, we will perform a genome-wide screen for novel cancer-driving ncRNAs leveraging existing large-scale data from several national and international cancer-genome-sequencing consortia. In tumor tissue, the normal functions of ncRNAs can be perturbed by different types of somatic alterations, for instance point mutations, DNA copy changes, genomic rearrangements, epigenetic changes, etc. Investigation of each of these diverse types of alterations requires specialized analytic approaches. To identify novel cancer-driving ncRNAs, we will specifically focus on a less well-studied type of alterations—genomic rearrangements. They include deletions, duplications, inversions, translocations and other more complex forms. A main consequence of genomic rearrangements is that they can shuffle the DNA content in the genome. We hypothesize that tumor-specific somatic genome rearrangements can reorganize ncRNAs and contribute to tumorigenesis. For example, we will systematically screen for new regulatory functions operating upon ncRNAs by relocation of regulatory elements in the genome due to somatic genome rearrangements. We will also screen for new ncRNA species created by shuffling of DNA fragments, which carry novel functions and contribute to tumorigenesis. Evolutionarily, exon shuffling has been an important mechanism to form new genes. Multiple complementary strategies will be implemented to overcome various scientific and technical challenges. Our study can lead to the discoveries of novel oncogenic ncRNAs, new biomarkers and potential drug targets, and reveal novel cellular process regulations in both normal and diseased conditions.