Research Corner

RNA Sequencing for Sarcoma Diagnosis: A New Frontier?

Authors: Yarenni Mendoza & Becky Gold

          July is Sarcoma Awareness Month! In November of 2007, all of the sarcoma nonprofits in Seattle joined forces to raise awareness for this type of cancer. Collectively, it was decided that this cancer of such rarity needed to have its own month dedicated to raise awareness - and so Sarcoma Awareness month was born. In observation of this, we will review a brand new study.

          Sarcoma is a type of rare type of cancer (approximately 1% of all cancer diagnoses) that occurs in many locations of the body, and fundamentally, it’s a cancer of the connective tissue - the cells that are involved in the connection or support of other tissues such as bones, muscles, tendons, cartilage, nerves, fat cells, and blood vessels. That being said, over 100 types of sarcoma cancers are recognized. This month we are focusing on a paper focusing on the work that is being done to appropriately diagnose sarcomas.

          RNA sequencing is a type of genetic test that allows us to look at all of the RNA (a nucleic acid much like DNA and precursor for protein production) in a given sample. This is useful for when you aren’t sure of the cancer causing mutation, whereas other methods frequently used for confirmatory testing in cancer - such as fluorescence in situ hybridization (FISH) - require knowledge of the causative mutation. For a cancer with so many variations and types such as sarcoma, this RNA sequencing is immensely useful.

          Because of its rarity and ability to form in different locations, sarcomas are often misdiagnosed. Effective treatment of sarcomas is also based on the diagnosis, so being able to effectively diagnose where the sarcoma is forming is essential to delivering the appropriate type of treatment for patients. When a sarcoma is in its earlier stages, symptoms are rather mild besides perhaps the presence of a painless lump. As the tumor grows, pain is more common, depending on if its pressing any nearby nerves. Diagnosis based on biopsy and histology (looking at cells of the tumor through a microscope) alone can be challenging and has shown to be ineffective. Sarcomas are diagnosed according to what type of healthy tissue the tumor tissue most resembles. For example, if the cancer cells look similar to adipose - or fat - tissue, sarcoma would be diagnosed as a liposarcoma. Certain proteins in or on the cells, called tumor markers, also aid in diagnosis. However, with over 100 distinct types of sarcoma, these diagnoses can be tricky to make. Sarcomas of the bone rely more heavily on medical imaging than soft tissue tumors, although histology and genetics are still important features of the diagnosis. 

          For this study, researchers used RNA sequencing to identify cancer-causing mutations for different types of sarcomas. They were looking at the utility and accuracy of making a sarcoma diagnosis using RNA sequencing in six different cases. They then also used methods that are currently the standard - FISH or DNA microarray - to confirm the oncogenic mutations found via RNA sequencing. Both of these standard methods are known to be accurate and valid. In five of the six cases, the researchers found the causative sarcoma mutation by the use of FISH and RNA sequencing. In the sixth case, an unexpected oncogenic mutation led to the ultimate diagnosis of a glioneural tumor - one which would likely not have been found using traditional methods. Of the first five cases, the RNA sequencing method successfully detected the fusion genes, which had been identified with traditional methods, and thus confirmed the formation of sarcoma. The detection of the causative mutation in the sixth case proved to be more challenging using standard methods. This case was sent to an academic institution to accurately determine the diagnosis. After the diagnosis was found, and it was tested with RNA sequencing, the results were corroborated the type of glial tumor identified at the academic institution. This research shows that the use of RNA sequencing allows researchers to diagnose different types of sarcomas and tumors in different locations of the body.

A major limitation of this study is the small sample size. With only six data points, it’s hard to know if this can truly be reproduced on a larger scale. Can this RNA sequencing method reliably identify over 100 types of sarcomas? Additionally, RNA sequencing - at this point - is still a fair bit more expensive than other types of confirmatory cancer genetic tests, meaning robust data would have to come forth supporting its superiority over other tests in order for insurance to cover it. Furthermore, while identifying the genetic information of a certain tumor may eventually allow us to administer very targeted treatments, we are still currently limited in our ability to target and treat sarcomas. Ideally, consistent access to the entire RNA sequence of a tumor profile may help drive compatible therapeutic research forward. 

          These findings have a few big implications. One is that it confirms what the researchers had hoped - RNA sequencing in this study was shown to be accurate and reliable in making a sarcoma diagnosis. Histology can be tricky with a lot of room for error in either the sample or interpretation, so RNA sequencing may offer a strong counterpart. Additionally, sequencing all of the RNA rather than searching for a specific mutation allows for the discovery of unusual mutations resulting in the anticipated type of sarcoma or, as we saw in the study, the discovery that the cancer is from an entirely different source all together. One day, it will also allow us to deliver precise and specific targeted therapy. Targeted therapy allows for treatment that yields fewer systemic and side effects, fewer late effects, and better outcomes. Finally, it could help us eventually identify more and differing oncogenic mutations not yet discovered that lead to various cancers, and perhaps be able to prevent the formation of other types of cancer. 

          The end game here would be to use RNA sequencing to determine the mutation causing the sarcoma, and then for therapy to exist to specifically target cells with that mutation. Likely - and hopefully - each of these will help drive forward the other. 

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