October 15, 1999
NEW ADVANCES IN COLON CANCER GENETICS
An inherited genetic mutation appears to be connected with certain familial late onset colorectal cancer cases, according to findings published in the current issue of Cancer Research.
“We have previously identified defective genes associated with more than half of the most common hereditary colorectal cancer cases, but these defective genes do not appear to be involved in cases of colorectal cancer which occur later in life in individuals with a weak family history, “ said Richard D. Kolodner, Ph.D., professor of medicine with the Ludwig Institute for Cancer Research at the UCSD School of Medicine, member of the UCSD Cancer Center, and lead author of the study. “This is the first genetic mutation we've found that is associated with an inherited susceptibility to colorectal cancer in this subset of patients who have weaker family histories of cancer.”
Colorectal cancer is one of the most common cancers, affecting one in every 16 people in the United States. Because it is so common, the occurrence of more than one case of colon cancer within an extended family is high; in about 20 percent of all cases, another family member with colon cancer can be identified.
In some of these cases, the multiple incidence within a family can be attributed to chance because of the frequent incidence of colon cancer in the population at large; however, in other cases there is a clear hereditary factor. This common hereditary cancer is called Hereditary Non-polyposis Colon Cancer (HNPCC), and the genes associated with this cancer are mismatch repair genes MSH2 and MLH1, previously cloned by Kolodner and his collaborators.
In this paper, Kolodner's team studied patients who are not HNPCC patients with a strong hereditary association, but who have one or more relatives with colon cancer.
“Because of the high prevalence of colorectal cancer, many familial cases may simply represent chance clustering. Dietary and other shared environmental influences
might also account for some family aggregates of these cancers,” the research team states in their report.
The team set out to determine if a gene mutation might be associated with some of these cases as well. They successfully identified a gene mutation in another mismatch repair gene called MSH6, associated with about 8 percent of the patients in the familial, but non-HNPCC, cases studied (20 percent of total colon cancer). This gene mutation did not occur in HNPCC cancer cases.
Mismatch repair genes serve the role of ensuring that during the process of normal cell division, the duplicate cell's DNA must be an exact replica of the original. According to Kolodner, these genes are the molecular version of a spell-checking program.
“If you have to retype a page of text without making a single mistake, it's difficult, and the chances are you will make a mistake,” he said. “The same is true with cell division; every time a cell divides, it has to copy its DNA perfectly. Mismatch repair genes serve the same purpose as a spell-checking program, ensuring that the duplication is exact.”
When these genes are defective, the duplication of a cell's DNA can go awry, resulting in greater cancer susceptibility. With this finding, it is possible to test for MSH6 mutations, identify carriers of this defective gene and monitor these individuals more carefully to detect early symptoms of cancer. It might also be possible through dietary and behavioral interventions to decrease the risk in these genetically prone individuals, he added.
This research was supported by grants from the National Institutes of Health, the Ludwig Institute, the Starr Foundation and the Liberty Mutual Group. It was done in collaboration with groups from UC Irvine, led by Hoda Anton-Culver, and the Dana-Farber Cancer Institute, led by Frederick P. Li.