New Hereditary Cancer Mutation Found for Lynch Syndrome

Scientists have combined genetic testing with genealogy detective work to discover a gene mutation that apparently was brought to the United States at least 13 generations ago by a German immigrant and may be responsible for a sizeable fraction of certain hereditary cancers in Americans.

People with the mutation have hereditary nonpolyposis colon cancer (HNPCC), a condition that places individuals at high risk for developing cancer of the colon, endometrium and ovaries.

HNPCC, also known as the Lynch Syndrome, named for Creighton University Medical Center’s hereditary cancer expert Henry T. Lynch, M.D., is the most common inherited colon cancer syndrome.

The mutation is not revealed by 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 Feb. 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.

So far, the scientists have identified 566 individuals in nine families who are descendents of that early immigrant. Of these, 137 have undergone genetic counseling and testing so far. The tests showed that 61 of the 137 carried the genetic mutation and should 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, M.P.H., genetic research associate at Creighton University, and one of the paper’s co-authors.

“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.

“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.”

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 have a strong hereditary component. HNPCC is thought to be the most common form of hereditary colorectal cancer. People with HNPCC have an 80 to 85-percent risk of colorectal cancer, a 56-percent risk of endometrial cancer, a 12-percent risk of ovarian cancer and a lower risk of other cancers.

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 these 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 genetic counseling and be retested for this specific mutation,” Coronel says.

The new mutation was discovered independently by researchers in the Netherlands, collaborating with Dr. Lynch at Creighton, who first described the HNPCC syndrome, and by researchers at Ohio State University, led by de la Chapelle.

At the time, unconventional genetic testing methods were used 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, likely descend 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. However, there may be family members with this mutation that would not know they were distant descendants of this 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 contact the Department of Preventive Medicine and Public Health at Creighton University Medical Center, call 800-648-8133 or e-mail scoronel@creighton.edu. To find the location of genetic counselors nationally, see the website for the National Society for Genetic Counselors at http://www.nsgc.org and use the “Find a Counselor” feature. Or go to the National Cancer Institute website at www.cancer.gov/search/genetics_services/