Two families, one gene

Tracking the EPCAM deletion in Lynch syndrome

In August 2005, Douglas L. Riegert-Johnson, M.D., a gastroenterologist and medical geneticist at Mayo Clinic in Jacksonville, Fla., met with a new patient. The 59-year-old woman had undergone surgery for cancers of the colon and small intestine resulting from Lynch syndrome, a hereditary genetic disorder.

People with Lynch syndrome have an 80 percent chance of developing early colorectal cancer and an increased risk of tumors of the endometrium, stomach, small intestine, liver and bile ducts, pancreas, and brain. The syndrome and ensuing cancers are caused by mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2.

As is common in Lynch syndrome, Dr. Riegert-Johnson's patient developed multiple intestinal cancers at a relatively young age. She also belonged to a large extended family — referred to as Family R — with a pattern of inherited colorectal cancer through five generations.

This long history of cancer was so striking that Henry Lynch, M.D., studied the family for more than four decades, mapping out the family tree and collecting and storing hundreds of samples. His research with Family R and similar families eventually led to the classic definition of the disorder that bears his name.

But although Family R met the clinical criteria for Lynch syndrome, two findings were atypical. First, despite the high incidence of colorectal cancers, only a few family members developed extracolonic tumors. More important, repeated testing failed to find evidence of MMR gene mutations, raising suspicions that the family had a new and undescribed form of Lynch syndrome. Without genetic confirmation, though, it was impossible to know which family members were affected.

"We had no way of identifying family members with the disorder until they actually developed colon cancer," Dr. Riegert-Johnson says. "And that was a critical problem because colon cancers in patients with Lynch syndrome can, for the most part, be prevented with annual or biennial colonoscopies, beginning around age 20. Since in this case we didn't know who had the disorder, all family members were encouraged to have lifelong screening colonoscopies, a regimen that presents many challenges."

He points out that colonoscopy requires preparation, sedation and time off work and carries risks of bleeding and colon perforation. "People are often reluctant to undergo these exams every year when the need for them is uncertain."

Family R struggled psychologically, too. "Because there was no way of identifying those most likely to develop cancer, family members worried about their own health, feared for their children and faced difficult decisions about conception," he says.

The missing genetic link

That began to change in late 2008 when Jacobus Ligtenberg and other researchers at the University of Groningen in the Netherlands reported a newly identified genetic alteration in a father and son with Lynch syndrome. The mutation — a deletion at the end of the epithelial cell adhesion molecule (EPCAM) gene — is next to a known Lynch syndrome gene, MSH2. Mutations in the EPCAM gene silence MSH2 by methylation.

Eventually, 10 members of the Dutch family — known as Family A — all with colorectal cancer, tested positive for the EPCAM deletion. Contrary to the typical Lynch syndrome pattern, only a few family members developed extracolonic tumors and none had endometrial cancer — the same anomalies observed in Family R in the United States.

And indeed, less than six months after Dutch researchers published their findings, Dr. Riegert-Johnson's patient became the first American to test positive for the EPCAM deletion. "Our lab did an extraordinary job of getting the EPCAM test up and running," he says. "But none of this would have been possible without the efforts of many groups of people working together."

One mutation, one ancestor

Dr. Riegert-Johnson accompanied Dr. Lynch when he traveled to Orange City, Iowa, to offer free testing to other members of Family R in 2009. Located in the northwestern corner of the state, Orange City prides itself on its Dutch heritage — evident in the town's architecture and lifestyle.

Dr. Riegert-Johnson says that it was impossible to spend much time among the windmills, clogs and tulips without making the unlikely, but inevitable, connection between Family R in Orange City and Family A in the Netherlands. "It didn't seem improbable that two separate families with this disease would both be Dutch," he notes.

Further testing confirmed that Family R and Family A had the same mutation, originating from a common ancestor nearly 10 generations earlier. In March 2010, Dr. Riegert-Johnson and Dr. Lynch returned to Orange City to give test results to 15 members of Family R. Others received their results through telephone counseling sessions. The sense of relief was immense, even for those whose tests were positive.

"The discovery of this genetic mutation and subsequent testing have been transformative for these families," Dr. Riegert-Johnson says. "They know who is at high risk of colorectal cancer and will benefit from surveillance tests. They also know that they don't have to worry about extracolonic cancers; we think because of the distance of the deletion from the MSH2 promoter. Most important, they're reassured about their own future and their children's. They just want to be around to ensure that their children have a good life."