Photo by Gordon Todd.
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If you have trouble deciphering this quote by Albert Einstein, you will appreciate the plight of a cancer cell as it struggles to make sense of the misspellings, gaps and repeats that riddle its genes.
Much like a newspaper's accuracy depends on a good editor, healthy cells employ their own proofreading strategies to rid DNA of errors that may rob their genetic blueprint-the genome-of its meaning. Without a dependable repair mechanism, a cell can spiral into a disorderly state of so-called genome instability. A hallmark of virtually all tumors, the condition results in rearranged chromosomes that lose the ability to orchestrate the normal growth pathways essential to a cancer-free existence.
To recognize their crucial roles in cancer, genome instability and its partner defect, mutagenesis (the process by which changes occur in DNA), are now the focus of a new addition to the roster of scientific programs supported by the Fred Hutchinson/University of Washington Cancer Consortium. Researchers in the program, led by Dr. Ray Monnat, UW professor of pathology, expect that a deeper understanding of a genome's transition to chaos will ultimately reveal new targets for cancer prevention and therapy.
Monnat said that the program formally pulls together scientists from both institutions with common interests in discovering how genome instability, mutagenesis and an individual's unique genetic composition-combined with environmental exposures-trigger the genome disarray that can give rise to cancer. The program also draws members from the Seattle Cancer Care Alliance and the Virginia Mason Research Foundation.
"The institutions already share a number of research facilities, collaborative grants and training grants for graduate students and postdocs," Monnat said. "By enhancing opportunities to interact and strengthening connections to our clinical colleagues, we'll be better positioned to translate the basic research into diagnostic and therapeutic applications."
Program members at Fred Hutchinson include Drs. Christopher Kemp and Helmut Zarbl, both investigators in the Human Biology and Public Health Sciences divisions, and Dr. Peter Rabinovitch, a joint member of Human Biology and a UW professor of pathology.
Dr. Lee Hartwell, Fred Hutchinson president and director and principal investigator of the Cancer Consortium, said the central roles of genome instability and mutagenesis in cancer make the addition of the program critical to a comprehensive cancer center.
"Genome instability is fundamental to the development of cancer," he said. "All solid tumors display enormous changes to chromosomes including breaks, deletions, amplifications and rearrangements; the only exceptions are tumors that display high levels of mutations without chromosome rearrangements. Because cells must accumulate a series of six or more mutations to become cancerous, it is probably essential that they become genetically unstable or they would not be able to undergo so many changes.
"While we have had a few people who work in this area at the center, the addition of our UW colleagues enormously increases the depth of expertise in this area."
Although cancer is always a disease of the genes, individuals may be born with a predisposition for genome instability or may acquire the condition over time as a result of environmental exposure (such as radiation or DNA-damaging chemicals) or the natural aging process.
Repair mechanisms in normal cells typically prevent harmful errors from being cemented in the DNA. But because a glut of mutations accumulate in cancer cells, researchers suspect that most cancer cells have defects in the very genes designed to safeguard them from damage, effectively robbing them of a proofreader. Unchecked, DNA-damaged cells continue to divide without restraint, sometimes giving rise to tumors. This theory, known as the mutator hypothesis, was proposed and developed by Dr. Lawrence Loeb, UW professor of pathology and associate head of the new Cancer Consortium program.
The mutator hypothesis is supported by a number of rare hereditary conditions that put individuals at high risk for cancer. Three such conditions-Werner syndrome, Bloom syndrome and Rothman-Thompson syndrome-are the focus of Monnat's research.
"Each of these conditions is caused by a deficiency in one member of a family of genes that code for proteins known as RecQ helicases," he said. "Although we don't know their precise function, it's clear that RecQ helicases have some role in maintaining genomes because we observe both stable and unstable chromosome rearrangements in individuals with these disorders."
Acquired or inherited defects in genes devoted to the faithful duplication of DNA, a process that must be completed prior to cell division, can also lead to genome instability. Mutations in the genes MSH2 and MLH1-which are required to repair errors introduced into newly duplicated DNA-have been linked to an inherited form of colon cancer.
While some inherited mutations independently trigger profound effects on genome integrity, many cause more subtle effects that are enhanced by certain environmental exposures, including smoking and diet. Such interactions are the focus of study at two research centers directed by program participants at Fred Hutchinson and UW.
The Comparative Mouse Genomics Center, co-directed by Kemp and Dr. Warren Ladiges, UW professor of comparative medicine, is developing mouse models to test hypotheses about the specifics of environment-genome interactions and their role in cancer and other diseases. Researchers will examine mice mutations identical to those found in human genes that control DNA repair and regulate the cell cycle. These efforts aim to determine if the mutations contribute to cancer risk in conjunction with certain environmental exposures.
Benefits of collaboration
Zarbl and Dr. David Eaton, director of the UW Center for Ecogenetics and Environmental Health, lead the Fred Hutchinson/UW Toxicogenomics Consortium, a collaboration dedicated to predicting an individual's risk of cancer based on his or her genetic profile and environmental exposures to such damaging agents as tobacco or asbestos.
Kemp predicts the establishment of the new program will boost research on these and other aspects of this important area of cancer biology in tangible and intangible ways.
"We already share equipment and resources with our colleagues at other institutions," he said. "Having a formal program devoted to genome instability and mutagenesis will enable us to secure multi-institutional grants to promote additional sharing of facilities.
"I also anticipate having more face time with my colleagues as a result of the program's formation. Anything that fosters more interaction is a positive thing."
Genome instability and mutagenesis activities
- Comparative Mouse Genomics Center, directed by Dr. Chris Kemp, of Human Biology and Public Health Sciences, and Dr. Warren Ladiges, UW professor of comparative medicine
- Fred Hutchinson/UW Toxicogenomics Consortium, directed by Dr. Helmut Zarbl, of Human Biology and Public Health Sciences, and Dr. David Eaton, associate dean for research, UW School of Public Health and Community Medicine
- The UW Genome Center, directed by Dr. Maynard Olson, UW professor of medicine and genome sciences
- The UW Center for Ecogenetics and Environmental Health, directed by Dr. David Eaton
- The UW Nathan Shock Center, directed by Dr. Peter Rabinovitch, a joint member of Human Biology and a UW professor of pathology
- The UW Program Project in Werner Syndrome, directed by Dr. Ray Monnat, UW professor of pathology