Unveiling non-coding drivers of cancer

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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.