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A research team led by Gunnar Rätsch, Professor of Biomedical Informatics at ETH Zurich, has evaluated the largest set of genetic data in cancer medicine. Through their analysis, they discovered new cancer-specific molecular changes that could potentially inform the development of cancer treatments.
Previous genetic analyses of cancer cells have concentrated on their DNA – the “basic” version of the genetic information. The studies examined genes to see if they contained tumor-specific mutations. In addition, it was studied if the genes were especially active or inactive depending on the tumor.
Now the ETH researchers have gone a step further and taken a closer look at the RNA molecules, which are responsible for transcribing the cell’s DNA. But before these molecules can serve as a blueprint for the biosynthesis of proteins, they undergo a series of transformative cellular processes: in a process called splicing, specialised enzymes cut out entire sections from the RNA molecule and join the sequences on either side together.
In their analysis for tumor-specific alternative splicing, Rätsch and his colleagues looked at an unprecedented volume of genetic cancer data, examining sequences in RNA molecules from 8,700 cancer patients. They found several ten thousand previously undescribed variants of alternative splicing that crop up over and over in many cancer patients.
The researchers were also able to show that in the majority of the cancer types tested, alternative splicing occurred much more frequently in tumor tissues than in healthy tissues. It is especially pronounced in pulmonary adenocarcinomas, where alternative splicing occurs 30 percent more frequently than in healthy samples.
Cancer leads to molecular and functional changes in cells. At the molecular level the changes come not only in the form of individual DNA mutations, which we’ve known about for a long time, but also to a great extent in the form of different kinds of RNA splicing, as we were able to show in our comprehensive analysis.
Not all of the newly discovered molecular changes in RNA necessarily also cause functional changes in cancer cells, the researchers say. Still, the molecular differences can inform novel therapy approaches – for instance, cells that feature splicing patterns typical for cancer could be treated with immunotherapy.
In targeted cancer immunotherapy, the body’s own immune system is trained to recognise typical molecular cancer markers so it can attack and kill cancer tisssue. Healthy body tissue is left alone. At present only a minority of cancer patients can be treated with this method, since tumor-specific markers suitable for use in immunotherapy were present in only some 30 percent of cases.
The newly discovered variations of alternative splicing lead to changes in proteins that in turn can also serve as tumor-specific markers: up to 75 percent of cases were found to exhibit these new markers that could potentially be used for developing specific medications.