Growing insights about a significant part of the genome, the dark matter of DNA, have fundamentally changed the way scientists approach the study of diseases. The human genome contains about 20,000 protein-coding genes, less than 2 percent of the total, however, 70 percent of the genome is made into non-coding RNA. Nevertheless, a systematic characterization of these segments, called long non-coding RNAs (lncRNAs), and their alterations in human cancer, is still lacking. Most studies of genomic alterations in cancer have focused on the miniscule portion of the human genome that encodes protein.
Now, an international team led by researchers at the University of Pennsylvania has mined these RNA sequences more fully to identify non-protein-coding segments whose expression is linked to 13 different types of cancer. The opensource study is published in the journal Cancer Cell.
Previous studies show that cancer is a genetic disease involving multi-step changes in the genome. The human genome contains 20,000 protein-coding genes (PCGs), representing less than 2% of the total genome whereas up to 70% of the human genome is transcribed into RNA, yielding many thousands of non-coding RNAs. Long non-coding RNAs (lncRNAs) are operationally defined as transcripts that are larger than 200 nt and transcriptional control of lncRNAs is subject to typical histone modification-mediated regulation. Importantly, rapidly accumulating evidence indicates that lncRNAs are associated with chromatin-modifying complexes and guide epigenetic regulations in both physiological and pathological conditions. Recent studies suggest that lncRNA is involved in the initiation and progression of cancer. In addition to the fact that they are highly deregulated in tumours. The team state that with non-coding RNA sequences constituting almost three quarters of the human genome, there is a great need to characterize genomic, epigenetic, and other alterations of long non-coding segments. The current study fills this significant gap in cancer research.
The current study analyzed lncRNAs at transcriptional, genomic, and epigenetic levels in over 5,000 tumor specimens across the different cancer types obtained from The Cancer Genome Atlas (TCGA) and in 935 cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE). Results show that lncRNA alterations are highly tumour- and cell line-specific compared to protein-coding genes. The lab note that in addition, lncRNA alterations are often associated with changes in epigenetic modifiers that act directly on gene expression. The group state that they believe the results from this multidimensional analysis provide a rich resource for researchers to investigate the dysregulation of lncRNAs and to identify lncRNAs with diagnostic and therapeutic potential.
The researchers also developed two bioinformatics-based platforms to identify cancer-associated lncRNAs and explore their biological functions. The lab explain that one is a searchable database that incorporates clinical information with lncRNA molecular alterations to generate short lists of candidate lncRNAs to study. They go on to add that the molecular profiling data used for this are linked to clinical and drug response annotations in the TCGA because of its high-quality, multiple-level profiles of human primary tumor specimens and detailed clinical notes for a broad selection of human cancer specimens, along with the CCLE, the best available resource for molecular profiles of cancer cell lines and details about their responses to drugs.
The second approach they developed, predicting the biological function of lncRNAs, successfully identified a novel oncogenic lncRNA called BCAL8. Data findings show that when BCAL8 is overexpressed it works to promote the cell cycle, which in turn controls cell division. This part of the study provided a proof of concept for the lncRNA search strategy, and a customizable database for other investigators to look for lncRNAs of interest and investigate their function. This database is called the Cancer LncRNome Atlas and is administered by the Abramson Cancer Center at Penn.
The team surmise that their findings provide convincing evidence that dysregulation of lncRNAs takes place at multiple levels in the cancer genome and that these alterations are strikingly cancer-type specific. For the future, the researchers state that they have laid the critical groundwork for developing lncRNA-based tools to diagnose and treat cancer in new ways. They go on to conclude that they expect additional important lncRNA discoveries will be enabled by their work.