U of M Cancer Researchers Discover 32 New Genes Linked to Colorectal and Liver Cancers

Scientists used unique identification method developed at the University

MINNEAPOLIS/ST. PAUL (March 9, 2009) --  Scientists at the University of Minnesota’s Masonic Cancer Center and Medical School report remarkable laboratory findings – 17 new genes that could cause colorectal cancer and 15 new genes linked to liver cancer – using the Sleeping Beauty method. The findings help pave the way for development of individualized, genetically based treatments for patients with these cancers.

Identifying genes associated with cancer is key to preventing some cancers and diagnosing others earlier in order to more successfully treat patients. The unique method used to make these new discoveries in laboratory animals relies on DNA transposons, commonly known as “jumping genes.” The specific transposon used, called Sleeping Beauty, is able to insert itself into or near genes to either activate or inactivate a gene’s normal function. This method was developed by University of Minnesota scientists and is proving to be a faster, more accurate and efficient method for identifying groups of genes associated with specific cancers.

The two research studies, sponsored by the National Cancer Institute, are published in the current online issues of the top-tier scientific journals Science and Nature Biotechnology. David Largaespada, Ph.D., leader of the Masonic Cancer Center’s Genetic Mechanisms of Cancer Research Program, is the senior scientist on both studies. He worked with lead University researchers Timothy Starr, Ph.D., to identify the colorectal cancer causing genes (Science article) and Vincent Keng, Ph.D., on finding the liver cancer genes (Nature Biotechnology article). Cancer researchers in the United States, Spain, and Singapore collaborated on these studies.

“At the root of all cancer is genetics – genes that we’ve either inherited that predispose us to certain types of cancer, or genes that have changed or mutated for some reason during our lives and initiate cancer,” Largaespada said.

“Different tumors have different sets of mutated genes, so we have to find all of the genes that can have a role in cancer,” he noted. “Our Sleeping Beauty method lets us hone-in on genes that we know are important to the genesis of tumors. It also provides us with important information about genes that other methods of gene identification do not, such as the specific combinations of gene mutations that work together to cause cancer in much finer detail.”

Colorectal cancer and liver cancer rank as the second and third leading causes of cancer death in the world. In the United States, nearly 150,000 people are diagnosed with colorectal cancer each year; more than 2,000 are Minnesotans. Liver cancer affects more than 17,000 people in the United States each year, but significantly more people throughout the world because of the increasing infection rates of the Hepatitis viruses that harm the liver.

Previous to this research, several genes were known to be associated with colorectal cancer. The study by Starr and his colleagues confirmed many of these known genes and added many new genes to the list of cancer-causing genes.

According to Starr, “Scientists are finding that every tumor has its own unique signature of gene mutations. By identifying more of the gene mutation signatures that are responsible for causing colorectal cancer, our study can help guide the design of new drugs and other therapies that could be used to treat a patient’s cancer.”

Prior to Keng’s finding, several genes had been linked with liver cancer. His study identified 15 new candidate genes.

“Using the Sleeping Beauty transposon-based insertional mutagenesis system, we were able to faithfully model all stages of human liver cancer,” Keng said. “With the identification of new candidate genes for liver cancer, two of which were functionally validated to contribute to the disease, this proof of principle study offers great potential for better understanding of the cancer genome.”

Largaespada added: “With cancer, one size does not fit all. The benefit of our findings is that it brings us another step closer toward an individualized approach to cancer treatment based on getting the right drug to the right patient at the right dose for maximum effectiveness.” 

More about Sleeping Beauty
Jumping genes, or transposons, are natural to the genetic makeup of humans, animals, and fish. However, through millions of years of evolution, most transposons became inactive dead-ends. In 1997, University of Minnesota researchers took defunct, non-functioning jumping genes from fish and made the genes jump again. That research reactivated the jumping genes from millions of years of evolutionary sleep – hence, the name Sleeping Beauty.

In 2005, David Largaespada and his colleagues reported on how specially designed Sleeping Beauty transposons were introduced into mouse DNA and made to jump around in the nuclei of mouse cells. Eventually the transposons jumped into cancer-causing genes and caused a tumor to form. By isolating and studying the genes from tumors that contained Sleeping Beauty, Largaespada and his colleagues were able to efficiently find genes linked to cancer by seeing whether Sleeping Beauty turned them on or off – in effect, uncovering the fingerprint of each tumor’s cancer genes. This newest research builds on that work.

Collaborating with Starr on the study, A Transposon-Based Genetic Screen in Mice Identifies Genes Altered in Colorectal Cancer, were: Raha Allaei, Kevin Silverstein, Rodney Staggs, Aaron Sarver, Tracy Bergemann, Gerard O’Sullivan, Ilze Matise,  Robert Cormier, and David Largaespada, all with the University of Minnesota;  Mihir Gupta, Harvard University, Cambridge, Mass.; Adam Dupuy, University of Iowa in Iowa City; Lara Collier, University of Wisconsin, Madison ; Scott Powers, Cold Spring Harbors Laboratory, Cold Spring Harbor, NY; Ann Oberg, Yan Asmann, and Stephen  Thibodeau, all with Mayo Clinic, Rochester, Minn.; Lino Tessarollo, National Cancer Institute, Frederick, Md.; and Neal Copeland and Nancy Jenkins, both with Institute of Molecular and Cell Biology in Singapore.

Collaborating with Keng on the study, Conditional Transposon-based Insertional Mutagenesis Screen for Genes associated with Mouse Hepatocellular Carcinoma, were Timothy Starr, Ilze Matise, Keven Silverstein, Aaron Sarver,  Barbara Ryan, and David Largaespada, all with the University of Minnesota; Augusto Villanueva, HCC Translational Research Laboratory in Barcelona, Spain; Derek Chiang, Dana-Farber Cancer Institutes, Harvard and MIT, Cambridge, Mass; Adam Dupuy, University of Iowa in Iowa City; Keiko Akagi and Lino Tessarollo, National Cancer Institute, Frederick, Md.; Lara Collier, University of Wisconsin, Madison; Scott Powers and Scott Lowe, Cold Spring Harbor Laboratory in Cold Spring Harbor, N.Y.; Nancy Jenkins and Neal Copeland, both with Institute of Molecular and Cellular Biology, Singapore, China; and Joseph Llovet, Mount Sinai School of Medicine in New York, and Institucio Catalana de Recerca i Estudis Avancats, Barcelona, Spain.

Masonic Cancer Center, University of Minnesota is part of the University’s Academic Health Center. It is designated a comprehensive cancer center by the National Cancer Institute. For more information about the Masonic Cancer Center, visit www.cancer.umn.edu or call 612-624-2620.

Contact:          
Mary Lawson, Masonic Cancer Center, 612-624-6165, mlwason@umn.edu
Sara Martin, Academic Health Center, 612-626-7037, buss@umn.edu