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 ge
Contact: Jon Weiner
University of Southern California