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.
About the National Cancer Institute Grant
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number R01CA170250. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
About the National Cancer Institute’s Provocative Questions Project
The Provocative Questions project emerged from discussion among a number of veteran cancer researchers that noticed there were many questions — some important but not very obvious, some that had been asked but abandoned in the past because we didn't have ways to study or address them, some sparked by new discoveries or novel technologies — that could stimulate the NCI’s research communities to use laboratory, clinical, and population sciences in especially effective and imaginative ways. Over the course of 18 months, NCI solicited questions from scientists in various fields and at different stages in their careers, ultimately settling on 24 questions that, if answered, could lead to significant research advances. In a departure from its traditional grant-making process, NCI released a special solicitation just for research related to these 24 questions and empaneled a custom set of peer review groups to score the more than 700 applications NCI received. More than 50 grants, attempting to answer 20 of the 24 proposed questions, are being funded this year from that set of applications. These grants are not intended to represent the NCI’s full range of priorities in cancer research, but rather represent a new and different way to identify and address research needs in cancer by challenging researchers to delve into key areas that require more in depth study.
About the UNM Cancer Center
The UNM Cancer Center is the Official Cancer Center of New Mexico and the only National Cancer Institute (NCI)-designated cancer center in the state. One of just 67 NCI-designated cancer centers nationwide, the UNM Cancer Center is recognized for its scientific excellence, contributions to cancer research and delivery of medical advances to patients and their families. It is home to New Mexico’s largest team of board-certified oncology physicians and research scientists, representing every cancer specialty and hailing from prestigious institutions such as MD Anderson, Johns Hopkins and the Mayo Clinic. The UNM Cancer Center treats more than 65 percent of the adults and virtually all of the children in New Mexico affected by cancer, from every county in the state. In 2010, it provided care to more than 15,800 cancer patients. The Center’s research programs are supported by nearly $60 million annually in federal and private funding. Learn more at http://cancer.unm.edu.