Sep 28 2012
Most of us think of DNA mutations as the culprits that cause cancer. Scott Ness, PhD, University of New Mexico Professor of Molecular Genetics and Microbiology and Associate Director at the UNM Cancer Center, thinks there may be another, more elusive culprit. If Dr. Ness is right his research, funded as part of the National Cancer Institute's Provocative Questions Project, might open a whole new arena in which to target anticancer drugs.
Currently, most genetic cancer research focuses on DNA (deoxyribonucleic acid) abnormalities. Dr. Ness' work will instead focus on RNA (ribonucleic acid), the molecule that transports the protein-making instructions to the structures that make the proteins. RNA is not an exact copy of DNA, however, and researchers have long known that the process to make RNA in normal cells differs from that in cancer cells. Whether these differences are important is the subject of Question 11 on the NCI's Provocative Questions list. Now, thanks to recent technological advances in genome sequencing, Dr. Ness will be able to study the impact of these RNA processing differences and whether they cause cancer.
The cell constructs RNA in a poorly-understood two-step process. In the first step, called transcription, the cell chooses the correct parts of DNA to use since only about 2 percent of the DNA encodes proteins. Genes are the sequences in the DNA that carry the protein-making instructions. In humans and all other vertebrates, genes are discontinuous. As a result, the RNA transcript must be refined and edited in the second step, a process called RNA splicing. In RNA splicing, the cell removes the non-protein-making parts of the gene-called introns-leaving only the protein instructions-called exons-strung together like boxcars in a train. Sometimes the RNA splicing machinery skips an exon or includes an extra exon that usually is not part of the final RNA. These changes, called alternative RNA splicing, are one of the mechanisms that allow genes to make multiple different RNAs and different types of proteins.
"One of the big surprises of the Human Genome Project was how few genes were discovered," says Dr. Ness. Researchers expected to find over 100,000 genes based on the number of different human RNA transcripts, but instead they found fewer than 25,000 genes. The discontinuity of genes and alternative RNA splicing explains how it's possible to have so many types of RNA from so few genes. "One gene can make different versions of RNA and then the RNAs are used to make the proteins," says Dr. Ness. "And so a gene might produce different kinds of RNA in different tissues, or in a fetus versus an adult, or in a tumor versus a normal cell."
In a normal cell, alternative RNA splicing occurs occasionally; in a cancerous cell, alternative RNA splicing happens much more often. "It's been known for a long time that tumors have much more alternative RNA splicing than normal cells do-ten times more. But no one knows if that's biologically important," says Dr. Ness. "No one knows if the controls in tumors are relaxed so that something is just not working properly and these RNAs are made by accident or if something more sinister happened in the tumor cells and these different RNAs are part of the cause of cancer."
To find out, Dr. Ness and his team will look in incredible detail at all the RNA produced in tumor cells-lots of tumor cells from hundreds of leukemia samples. Using the next-generation Ion Proton Genome Sequencer expected at the UNM Cancer Center later this month, Dr. Ness's team will sequence the RNA in the samples to determine which proteins the leukemia cells made. Then, using complex statistical analyses combined with data on the patients' outcomes, he and his team will be able to determine whether increased levels of alternative RNA splicing contribute to cancer formation.
The implications of Dr. Ness's work are far-reaching. In his previous work, he and his team studied an oncogene named c-myb. This gene controls the proteins that bind to different other genes to turn them on or off; it decides which proteins the cell makes. The c-myb gene itself may not have a mutation, Dr. Ness found, but the RNA transcripts made from it might be very different in a cancer cell compared with a normal cell because of alternative RNA splicing. The mechanisms for controlling RNA splicing-and whether alternative exons are encoded-is not very well understood. But, if alternative RNA splicing is important, study of this area could give researchers greater insight into cancer mechanisms and a whole new array of cellular machinery against which to target cancer drugs.