USC consortium receives $15 million NCI grant to determine causes of colon cancer

October 25, 2002

Los Angeles, Oct. 25, 2002--The National Cancer Institute (NCI) has awarded $15 million to the University of Southern California as part of a $50 million renewal grant for the Cooperative Family Registries for Colorectal Cancer Studies, an international collaboration between six different centers, including a consortium of researchers from USC and several other institutions.

"This is the largest single resource in the world to help determine what causes colon cancer and how to prevent it," said Robert Haile, DPH, professor of preventive medicine in the Keck School of Medicine of USC and the principal investigator for the USC consortium.

The registry, which was established five years ago, now consists of some 8,000 families in which at least one and, most often, several members have been diagnosed with colorectal cancer. Overall, said Haile, the registry has upwards of 15,000 colorectal cancer patients on its rolls. Each cancer patient fills out a questionnaire and gives blood samples (which are then made into blood cell lines for detailed study in the laboratory); in addition, pathology reports and tumor samples are collected by the registry.

"The first five years of the grant were used building up this incredible resource," said Haile, who is also chair of the registry's steering committee, which does all the decision-making for the registry and provides its scientific leadership. "Over the next five years, the emphasis is going to be more on the research components: on using the tissues and data collected to understand what causes colorectal cancer, with an emphasis on genetic factors and gene-environment interactions, and on launching prevention trials based on what we find."

This sort of research focus makes the colorectal cancer family registry unique, said Daniela Seminara, Ph.D., MPH, the registry's program officer from the NCI's Division of Cancer Control and Population Sciences. "This registry is particularly important because of the molecular characterization that will be done in the next four to five years and the way the population will be followed up to look for further cancer development," she explained. "In addition to being a retrospective study, it will become a prospective study."

One of the immediate goals of the USC consortium, said Haile, is to begin looking at a set of genes known as the mismatch repair genes. The mismatch repair genes are responsible for the repair of DNA when they are in their normal form; when they're mutated, they seem to predispose the person carrying them to develop colon cancer. "The mismatch repair genes are sort of the parallel story to the BRCA breast cancer genes," said Haile. "As with BRCA mutations, we don't know the penetrance of mutations in these genes-what the lifetime risk of getting colon cancer is for carriers of these mutated genes. Finally, we want to figure out what affects that risk: Do exercise, diet or other lifestyle choices lower the risk? Do smoking, diet or other lifestyle choices raise the risk?"

The decision to go after the mismatch repair genes was by no means random: Deficiencies in the mismatch repair genes are the underlying cause of what is known as microsatellite instability, the result of an error in DNA replication. And high levels of microsatellite instability are found in 20 percent of all colorectal cancer cases.

Haile notes, however, that not all of this microsatellite instability is the result of mutated mismatch genes. Indeed, he said, there are "lots of families" in whom the gene is somehow silenced rather than mutated-most likely due to a process known as DNA methylation, in which methyl groups are tacked onto critical stretches of a gene, preventing it from being replicated or turned on. One of the questions the registry's researchers will be addressing in the next few years, said Haile, is how many of the 20 percent of colon cancers with microsatellite instability are the result of gene mutations, and how many are the result of methylation.

Even more critical, however, are the differences between that 20 percent of patients and the 80 percent with stable microsatellites. "The underlying causes of the colon cancer are different, at the molecular level, for patients who have a high level of microsatellite instability and those who are microsatellite stable," said Haile.

"Molecularly, it's like a different disease. And the clinical course seems to be different in these groups. That's why the registry has been funded to, among other things, test for microsatellite instability in all the colorectal cancer cases we find. We'll use that information to divide the cases and look for the different causes for each type and look at the different outcomes."

Other arms of the registry will consider some of the behavioral aspects of this disease, as evidenced in its widely diverse population. Among the things that researchers will be looking into, said Haile, are the ways in which people at high risk for colorectal cancer perceive that risk, how the information about risk is transmitted, and who decides to get screened for the cancer and why. "There's a much lower compliance rate with screening for colorectal cancer than there is for breast cancer," Haile said. "It's crucial to understand that if we're going to translate our work for the public and try and get families to follow preventive guidelines, including screenings."

Being able to apply the findings from these affected families to the population at large is the key to the power of this registry, added Seminara. "It's a very complete registry," she said. "It combines the epidemiological risk factor data with biospecimens, and its findings can be translated to the general population. That makes this registry very important for public health purposes."
The USC consortium includes researchers from the Keck School of Medicine and the USC/Norris Comprehensive Cancer Center as well as from the University of North Carolina, the University of Colorado, the University of Arizona, the University of Minnesota, Dartmouth Medical School and the Cleveland Clinic. The other five centers involved in the registry include: the University of Hawaii; the Fred Hutchinson Cancer Research Center; the Mayo Clinic; the University of Queensland, Brisbane, Australia Consortium; and Cancer Care Ontario.

University of Southern California

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