NOTNew research suggests that transposable elements – or so-called “jumping genes” – could help scientists identify tumor-targeting proteins. The study, published Monday, March 27 in Natural genetics, suggests that during cancer, transposable elements make their way into genes and can then be translated into tumor-specific antigens, which are proteins on the surface of the tumor that mark the cell for immune destruction. The results could help researchers design more generalized cancer therapies in patients with a particular type of cancer than current treatments, the study authors suggest.
Transposable elements (TEs) are short, repetitive sequences that can copy to other regions of the genome. Normally, ETs are epigenetically silent. But when a cell becomes cancerous, it can start jumping to different regions of the genome. According to the study, many tumor-specific antigens arise when a transposable element inserts into the coding region of a gene, making its way to the final protein product.
“It has been previously shown that certain transposable elements are translated and can be presented to cells of the immune system. What was impressive was the scope of the analysis,” says Claude Perreault, immunogeneticist at the University of Montreal, who did not participate in the study. “I think they did a superb job.”
Study co-author ting wang, a geneticist at Washington University School of Medicine in St. Louis, didn’t start studying cancer. Instead, he had long been interested in how transposable elements contribute to evolution, particularly in the context of regulatory elements. Then, five years ago, he and his lab made several discoveries about how transposable elements disrupt regulatory elements during cancerwhich he calls “another form of evolution”.
See “Adjusting with a little help from Jumping Genes”
From previous work in the lab, he knew that when transposable elements destabilize regulatory elements, they allow expression of regions of the genome that would normally be dormant. Sometimes this aberrant transcriptional regulation results in a chimeric transcript, in which a transposable element sticks onto a normal gene, resulting in a mix of a regular gene and a jumping gene, Wang says.
Although the exact mechanism behind this phenomenon is unclear, transposable elements are often found in introns, which may not be spliced. The researchers had observed this phenomenon before, but they had not yet characterized its frequency, which Wang set out to do.
For the study, Wang and his colleagues analyzed data from The Cancer Genome Atlas (TCGA), a large open source database containing genetic sequences from various human tumor samples. Using bioinformatics approaches, scientists searched mRNA sequencing data from more than 10,000 samples in 33 tumor types, as well as matched control tissues, looking for chimeric transcripts.
The approach was the reverse of a typical mRNA sequencing analysis, says Wang. “Typically, people use RNAseq data to map genes and understand the level of gene expression,” he says. “But in this case, what we’re hoping to do is discover a new gene product. So instead of mapping the data to the genes, we created the transcript’ and then mapped the new transcript to the data.
The results shocked Wang. Across all cancer types, he and his colleagues found about 2,300 different chimeric transcripts that were unique to tumors, far more than expected. In addition, 98% of tumors exhibited at least one chimeric transcript event. Many of these chimeric transcripts were shared between tumors of the same cancer type.
But that only told the researchers that the chimeric transcript was being transcribed, not translated. So, using publicly available cancer cell line data from the Genentech Cell Line Bank, another publicly available dataset, the team searched available mRNA sequencing data to find chimeric transcripts in the cancer cell lines. Once they found these transcripts, they predicted that some would be regulatory elements, as they had found in their previous studies. Using nanoCAGE sequencing, a genome-wide promoter analysis method, they indeed discovered that some of the chimeric transcripts provide tumor-specific promoters.
Then they went in search of tumor-specific antigens. After getting the cell lines in the lab, they used MHC pull-down, which is a technique for isolating proteins on the surface of tumor cells. Next, they identified the antigens using mass spectrometry, finding evidence that tumor-specific antigens were translated from chimeric transcripts.
See “The role of jumping genes in cancer”
Wang mentions that the authors have not yet tested whether the proteins directly elicit an immune response. However, Perreault says he would be “optimistic” because other groups have found proteins derived from transposable elements to be immunogenic. He also hopes the authors will extend their analyzes to other cell lines and primary tumors in the future.
Wang hopes the findings will improve cancer therapies down the road, as immunotherapies such as CAR-T cell therapy and cancer vaccines rely on tumor-specific antigens, but says there are many steps needed. before it becomes a reality. Identifying specific mutations is effective in cancers with a high mutation load, such as melanoma, but less effective in other cancers with a low mutation rate, such as glioblastoma and pediatric cancers. Chimeric transcripts are an abundant source of new antigens, sometimes more abundant than tumor-specific antigens induced by mutations, he says.
“Mutation-related events are often very patient-specific,” says Wang. According to the research, chimeric transcription events are much more recurrent in tumors of the same cancer type, which may allow researchers to design therapies that work for multiple patients with the same cancer.
“A new antigen is a big deal,” says Wang. “Immunotherapy has truly changed the way we treat cancers. Many immunotherapies rely on identifying new antigens, which is why people sequence the cancer genome to try to identify mutations that give rise to new antigens.