Unlocking the
Mysteries of
Extracellular RNA
Communication

Once thought to exist only inside cells, RNA is
known to travel outside of cells and play a role in newly
discovered mechanisms of cell-to-cell communication.

Exosome Diagnostics

Exosome Diagnostics, Inc. has announced the launch of ExoDx Lung(ALK), the first ever CLIA-validated exosome based blood test. This test detects EML4-ALK fusion transcripts in the plasma of lung cancer patients whose primary tumors carry this mutation. Although these patients make up a small minority of cases, identifying them is important because their tumors are particularly sensitive to ALK inhibitors. Current clinical tests are performed on biopsied tumor tissue. Major drawbacks include not only the risks associated with the invasive biopsy procedure but also low test performance for some of the commonly used methods (especially immunocytochemistry-based tests). In contrast, ExoDx Lung(ALK) requires only a standard blood draw and has 88% sensitivity and 100% specificity (as reported by the manufacturer). This is a major milestone in the application of exosome-based biomarkers to precision medicine, especially in the areas of companion diagnostics and targeted therapies.

The key discovery that let to this test was made eight years ago when Dr. Johan Skog, the Chief Scientific Officer at Exosome Diagnostics, demonstrated that a mutation present in the tumors of patients with glioblastoma could be detected in their blood (Skog et al., 2008). The publication reporting this finding has been cited over 1600 times, indicating its significance and potential for broad application. Now lung cancer patients can directly benefit from the first clinical test based on this discovery, in the form of a non-invasive test to determine the EML4/ALK mutation status of their tumors. We are sure that many more biofluid-based tests, targeting not only cancers but also other conditions where non-invasive testing is desired, will soon follow.

exRNAatlas

The first public release of the exRNA Atlas is now available via the ExRNA Atlas link in the Quick Links section of the exRNA Portal. The Atlas is produced by the NIH Common Fund’s Extracellular RNA Communication (ERC) Consortium and includes 519 small exRNA profiles from eight laboratories. Each profile in the exRNA Atlas acknowledges the contributing laboratory. The profiles were derived from about 6.4 billion reads uniformly processed using the exceRpt small RNA-seq pipeline. Faceted filtering and data navigation tools — hosted by GenboreeKB — are enabled by rich metadata standards developed by the consortium and metadata annotations contributed by the data producers. Uniform data quality metrics agreed by the consortium were applied to all datasets. On behalf of the Bioinformatics Research Lab at Baylor College of Medicine and the whole Data Management and Resource Repository (DMRR), I would like to thank the contributors and the consortium for the outstanding team effort required to reach this important milestone!

To balance the desire of data contributors to have a protected period of time to analyze and publish the data they have produced, the data access policy for datasets in the exRNA Atlas provides for a 12-month embargo period. The embargo period expires on 1 July, 2016 for the profiles in the current release. Researchers may analyze embargoed datasets from the Atlas but may not publish or make scientific presentations about them until the embargo period has ended. The Atlas will be updated regularly with new profiles, each new profile having its own 12-month embargo period per the data access policy. The read-level information for the profiles in the Atlas will be deposited in GEO (unrestricted access) or dbGaP (controlled access). The exRNA Atlas profiles will contain links to these archival records as the data are deposited.

The exRNA Atlas website is currently optimized for the Firefox browser. Extensive testing on other browsers is yet to be performed. Not too many problems are expected on other browsers, but if you do encounter a problem, consider using Firefox. Optimization for mobile devices is also yet to be completed.

Sai Subramanian of the DMRR highlighted the features of this new release of the exRNA Atlas on an ERCC webinar on 4 Feb, 2016 at 1pm ET. If you missed the live talk, it will be available soon afterwards at exRNA.org/About.

Where do we go from here? Of course, we are just at the beginning. By the end of 2016, the amount of data from the consortium’s reference profile projects will likely dwarf this first release. Our next focus here at the DMRR will be to “test drive” the data by performing a number of integrative analyses and to deploy analysis tools that may be applied both to the Atlas profiles and to profiles that are not yet public. Stay tuned and Happy New exRNA Year!

Non-coding RNAs (ncRNAs), for example microRNAs (miRNAs), are frequently dysregulated in cancer and other diseases, and have shown great potential as tissue-based markers for cancer classification and prognostication. ncRNAs are present in membrane-bound vesicles, such as exosomes, in extracellular human body fluids. Circulating miRNAs are also present in human plasma and serum and cofractionate with the Argonaute2 (Ago2) protein and high-density lipoprotein (HDL). Since miRNAs and other ncRNAs circulate in the bloodstream in highly stable forms, they may be used as blood-based biomarkers for cancer and other diseases. A knowledge base of non-invasive biomarkers is a fundamental tool for biomedical research in this field.

In 2012, miRandola was developed as the first database of circulating extracellular miRNAs (Russo et al., 2012). miRandola is a comprehensive, manually curated collection and classification of circulating extracellular miRNAs. We recently updated miRandola with 271 papers, 2695 entries, 673 miRNAs and 12 long non-coding RNAs. The future direction of the database is to be a resource for all potential non-invasive circulating nucleic acid biomarkers.

miRandola_schema

miRandola is the first online resource which gathers all the available data on circulating RNAs into one environment (see Figure). It represents a useful reference tool for anyone investigating the role of extracellular RNAs as biomarkers, as well as their physiological function and their involvement in pathologies.

The database is constantly updated as soon as new data is available, and the online submission system is a crucial feature which helps to ensure that the system is always up-to-date. We are working on a second version of the database to increase the amount of data and to improve usability. miRandola is available online at http://atlas.dmi.unict.it/mirandola/.