Cancer Genome Atlas reveals ‘splicing’ weakness in tumors

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Researchers have discovered cancer-specific molecular changes that could inform the development of new cancer treatments.

Gunnar Rätsch, professor of biomedical informatics at ETH Zurich, led the research team as they evaluated the largest set of genetic data in cancer medicine: the Cancer Genome Atlas in the United States . The Atlas compiles genetic information on tumor cells from several thousand cancer patients and 33 types of cancer at the DNA and RNA level.

Many previous genetic analyses of cancer cells have concentrated on their DNA—the “basic” version of the genetic information, so to speak. Such studies examined genes to see if they contained tumor-specific mutations. In addition, researchers examined whether the genes were especially active or inactive depending on the tumor.

Now, the new research goes a step further and takes a closer look at the RNA molecules, which are responsible for transcribing the cell’s DNA.

What’s the Cancer Genome Atlas?

Over its 13 years, the Cancer Genome Atlas compiled and analyzed genetic data from tumor tissue and normal tissue from several thousand American patients. The US National Cancer Institute’s Center for Cancer Genomics and the National Human Genome Research Institute supervised the work.

The project came to a close at the end of last year as planned; however, the collaborating institutes announced that there will be follow-up projects building on the Atlas and the insights it produced. By collecting and analyzing the numerous molecular changes that drive various forms of cancer, the project aimed to lay the foundation for their early detection, prevention, and treatment.

Alternative splicing

Before RNA molecules can serve as a blueprint for the biosynthesis of proteins, they undergo a series of transformative cellular processes: in a process called splicing, specialized enzymes cut out entire sections from the RNA molecule and join the sequences on either side together. An RNA molecule can be spliced in a range of different ways, which experts refer to as “alternative splicing”.

Molecular differences can inform novel therapy approaches—for instance, cells that feature splicing patterns typical for cancer could be treated with immunotherapy.

In other words, as a copy of a gene, an RNA molecule can deliver the blueprint for various protein forms, the groundwork for which is laid during splicing.

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 tens of thousands 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.

Thanks to this study, the researchers gained new insights into which molecular factors cause the high rate of alternative splicing in cancer cells. Researchers already know about some genetic mutations that encourage alternative splicing, but now the team was able to identify another four genes involved.

New immunotherapy targets

“Cancer leads to molecular and functional changes in cells. You could say that in cancer cells, there’s lots of sand in the gears,” says André Kahles, a postdoctoral researcher in Rätsch’s group and a lead author of the study. “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.

Team discovers roughly 100 potential cancer culprits

In targeted cancer immunotherapy, the body’s own immune system is trained to recognize typical molecular cancer markers so it can attack and kill cancer tissue. Healthy body tissue is left alone.

Currently, only a minority of cancer patients can benefit from 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: researchers found that up to 75 percent of cases exhibited these new markers that could potentially pave the way for developing specific medications.

Simply obtaining information on the frequency of alternative splicing is in itself highly valuable. Specifically, the scientists theorize that tumor tissue with many splicing operations is particularly vulnerable to another type of immunotherapy, namely non-targeted immunotherapy.

For the study, the researchers analyzed several hundred terabytes of raw data.

“To analyze such huge volumes of data, we needed an enormous amount of computer time and fast storage systems. Without a supercomputer, the study would not have been possible,” Rätsch says. He and his colleagues came to ETH Zurich two years ago from Memorial Sloan Kettering Cancer Center in New York, where they had started the study. Once in Switzerland, they joined forces with ETH’s IT Services to set up the Leonhard Med computer system, which let them securely process gigantic sets of genomic and other medical data.

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The research appears in the journal Cancer Cell.

Source: ETH Zurich