Columbus, Ohio – Scientists have combined genetic testing with genealogical detective work to discover and trace the source of an unusual gene mutation. That mutation apparently was brought to the United States at least 13 generations ago by a German immigrant, and it may be responsible for a sizeable portion of certain hereditary cancers in Americans.
People with this mutation are at high risk for developing cancer of the colon, endometrium and ovaries. The condition is known as hereditary nonpolyposis colon cancer, or HNPCC.
The mutation is not normally revealed by using typical genetic testing methods. However, the researchers have developed a relatively simple and inexpensive test that detects its presence.
The findings are published in the February 11 issue of the Journal of the American Medical Association. The study represents a collaboration among researchers at Creighton University Medical Center, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and Leiden University and Erasmus University Medical Center, both in the Netherlands.
"Our challenge now is to determine how common this mutation is in the United States," says Albert de la Chapelle, co-director of the OSU Comprehensive Cancer Center's Molecular Biology and Cancer Genetics Program and a co-author of the paper. "The good news is we have a simple way of detecting it, and we are now devising strategies to comb the nation for this mutation."
So far, the scientists have identified 566 individuals in nine families who are descendents of that one early immigrant. Of these, 137 have undergone genetic counseling and testing so far. The tests showed that 44.5 percent (61 of the 137) carry the genetic mutation and should therefore receive regular check-ups for colorectal, endometrial and ovarian cancer.
"Knowledge about this mutation will help us identify more high-risk individuals who need education about HNPCC and the steps they can take to protect themselves against the cancers associated with the syndrome," says Stephanie M. Coronel, genetic research associate at Creighton Medical Center and one of the paper's co-authors.
An estimated 147,500 cases of colorectal cancer occurred in the U.S.A. in 2003, and up to 25 percent of those were thought to be hereditary or to have a strong hereditary component. HNPCC is believed to be the most common form of hereditary colorectal cancer. People with HNPCC have an 80-85 percent risk of colorectal cancer and, among women, a 56 percent risk of endometrial cancer and a 12 percent risk of ovarian cancer.
The new mutation is known as a deletion mutation, in which part of a gene is lost. The new HNPCC deletion mutation results in the loss of about one third of a gene known as MSH2.
The discovery of the new mutations should improve the detection of HNPCC, which is usually diagnosed based on a person's family history or the presence of certain gene mutations in one of five genes, or both.
However, most people with a family history of the disease do not have an easily detectable mutation, and the genetic tests for mutations are expensive. Furthermore, these tests usually do not detect deletion mutations. The new test for the deletion mutation is less expensive than the usual HNPCC genetic tests.
"We hope that families who have already been tested and for whom no mutation was found will return for a genetic consult and be retested for this specific mutation," Coronel says.
The new mutation was discovered independently by researchers in the Netherlands collaborating with Henry T. Lynch at Creighton Medical Center, who first described the HNPCC syndrome, and by researchers at Ohio State University, led by de la Chapelle.
At the time, both groups were using unconventional genetic testing methods to study mutations associated with HNPCC, methods that also detected deletion mutations.
Ultimately, Lynch's group found seven families in their database with the mutation, and the Ohio State group found two families. The nine families then helped the investigators launch a major historical and genealogical study to trace their ancestry.
This evidence allowed the researchers to conclude that the mutation was in either the husband or wife of a couple that had immigrated from Germany and settled in Pennsylvania in 1727. The couple had 11 children.
In the end, the researchers could prove that three of the affected families descended from that one founder couple. The genealogies so far compiled for the remaining six families show that they, too, in all likelihood descended from the founder couple. The couple's descendents moved out across the United States, some going first to North Carolina, while others headed west to Kentucky, Tennessee, Missouri, Iowa, Nebraska, Texas, Utah and California. Today, some members of almost all nine families reside somewhere along this route.
The researchers, however, believe that there are family members with this mutation throughout the United States, and that most would not know that they had descended from the original German couple. People with cancers of the colon, rectum, endometrium and ovaries or who have a family history of these cancers, should consider seeking a consult with a local genetics counselor to determine if they should be tested for the new mutation.
To find the location of genetic counselors nationally, see the website for the National Society for Genetic Counselors and use the "Find a Counselor" feature. Or go here at the National Cancer Institute website.
The above story is based on materials provided by Ohio State University. Note: Materials may be edited for content and length.
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