Family's genetic death sentence—and genetic escape
This photo of the Bradfield family, taken Sept. 20, 1942, includes (front row) Phil and Warren; their parents Loren and Golda, and Larry, another son. In the back row are five more of the couple’s children: Dorothy; Don; Becky; Betty and her husband Bob Allen, and Eula. Seven of those pictured died of stomach cancer. Those that did not die from the cancer include Loren, the father who never carried the gene; Warren; Bob, and Don, who died of a heart attack but passed the gene for the cancer on to his children.
Golda Bradfield's death in 1960 from stomach cancer foreshadowed a legacy she would pass on to the next three generations of her family. She never knew that she had a mutation in a gene known as CDH1 that made stomach cancer almost inevitable. So far, 21 of her 31 children, grandchildren and great-grandchildren have inherited that mutation.
Of Bradfield's seven children who unknowingly carried the mutation, six died of stomach cancer, mostly in their 40s and 50s. It is not known whether the eighth child, who had no children, had the gene.
As Bradfield's 18 grandchildren watched their parents, aunts and uncles fall ill, the threat of stomach cancer seemed ever-present. "I felt like this big cloud was hovering over me since I was 13 when my mother was diagnosed," said Mike Slabaugh, Golda Bradfield's grandson who lives in Dallas. His mother died two years later. He said he never married and never had children because of his concerns about cancer.
Despite his fears, Slabaugh is still alive, as are all but one of his 17 cousins. Slabaugh and his cousins' experience with cancer differed dramatically from that of their parents, who had little warning of when or if cancer might appear. Instead of living or dying at the whim of their genetics, the cousins have turned recent genetic technology to their advantage. They have all been able to be tested for the mutation.
For those inheriting the mutated gene, knowledge means power. They had their stomachs removed before discovering signs of cancer, evading their genetic destiny.
The Bradfield family's experience with genetic testing is one that is becoming more common as research yields increasing numbers of disease-causing genes. Groups such as the Stanford Cancer Genetics Clinic now offer testing for many mutations and have projects under way to learn more about treating and preventing cancer in people who carry those mutations. According to assistant professor James Ford, MD, who leads the clinic, Stanford was among the first to counsel families with inherited genes that increase their chance of stomach cancers—and offers some an operation to eliminate the risk.
That was an offer the Bradfield cousins who tested positive for the CDH1 mutation accepted. Six of the cousins including Slabaugh had their stomachs removed at Stanford by surgeon Jeff Norton, MD. For them, as with others, testing meant an end to constant worries about the future. "The specter of gastric cancer is gone forever. When I wake up in the morning, it's a day I wouldn't have had," Slabaugh said.
The Bradfield cousins and their families are meeting in Las Vegas on May 27 to celebrate overcoming the odds. For some, this reunion will be the first face-to-face meeting, despite regular e-mails and phone calls. Linda Bradfield, one of the cousins who tested positive for the mutation, said the family only started talking regularly after the diagnosis. "We weren't a close family," she said. "It's tied us together."
Stomach cancer has been known to run in families for centuries. Napoleon Bonaparte's family is now thought to have carried the CDH1 mutation. But it wasn't until 1998 that researchers in Australia discovered the gene in a New Zealand Maori family with extensive stomach cancer. Since then, a few researchers have begun offering testing for the mutation. About 100 families have tested positive.
The CDH1 gene makes a protein called E-cadherin that normally dots the outside of cells, helping those cells bind to each other in a sheet. Golda Bradfield had one copy of the gene that made a normal E-cadherin protein and one that carried the mutation. Statistically speaking, each of her children had a 50/50 chance of inheriting either the mutated copy or the normal copy of the gene.
The Bradfield cousins became aware that a mutation was responsible for their family's cancer risk in 2003 when the first in their generation died of gastric cancer. His doctor sent a blood sample to David Huntsman, MD, at the University of British Columbia, then one of few to offer a test for mutations in the CDH1 gene.
Although the family member had died by the time the result came back positive, his wife sent a letter to the remaining Bradfield relatives. In it she included information from UBC describing the CDH1 mutation and recommending genetic counseling for all family members.
Linda Bradfield in Anaheim Hills, Calif., was among the first to get tested. She and her sister Rita, visiting from Seattle, and a third sister Stephanie, of Newport Beach, Calif., had blood drawn on President's Day of 2004. Six weeks later they got the results. Rita and Linda were positive, Stephanie was not.
"I know it was hard for the genetic counselor to tell us," Linda Bradfield said. "Had there not been something we could do about it, I don't know if I would have wanted to know."
Before getting tested, the sisters had already been counseled that preventing the cancer likely meant removing the entire stomach in a surgery called a gastrectomy, normally performed only on people with advanced stomach cancer. Although knowledge of the CDH1 mutation was still relatively new, a few papers, including one by Ford in 2002, advocated the procedure because of the 70 to 80 percent risk of developing stomach cancer.
"I knew right away I'd get the surgery," Bradfield said. The risk of stomach cancer scared her more than life without a stomach. As luck would have it, Bradfield's genetic counselor had heard a talk by Ford when the Stanford geneticist visited Hoag Cancer Center in Newport Beach. Bradfield contacted Ford and came to Stanford to discuss treatment.
On Aug. 4, Bradfield became the first of six of the cousins to have her gastrectomy performed by Norton. She narrowly missed being the first cousin to take the plunge altogether: Her sister Rita had the surgery a month earlier at the University of Washington in Seattle.
Both of the sisters' surgeries were delayed several weeks by university reviews. Because testing for CDH1 was relatively new, and prophylactic gastrectomy all but unheard of, the surgery was considered experimental. Ford and Norton had to get sign off from Stanford's Institutional Review Board, which approves all experimental procedures, before they could proceed. Rita faced the same delay in Washington. Ford and Norton eventually convinced the IRB and Bradfield's insurer that a gastrectomy was the only option for preventing her cancer.
Ford said in the case of CDH1 and other newly discovered mutations, the genetics is often ahead of the treatment. After discovering the mutation and developing a test, it can take several years before the genetics community reaches a consensus on how to treat people at risk. During that time, getting insurance to pay for the increased screening or prophylactic surgeries can take work.
Following Linda's surgery, three female relatives who tested positive had the surgery at Stanford on Nov. 29 and 30 and Dec. 1, 2004. On Valentine's Day of the following year, Slabaugh and his cousin Mark Allen, whose deceased brother was the first to test positive for the mutation, became Norton's fifth and sixth patients.
In the end, all 11 cousins who inherited the CDH1 mutation went ahead with the gastrectomy. Before the surgeries at Stanford, doctors ran a battery of tests to detect potential tumors. They peered into the stomach via endoscopy, took random biopsies to test for cancerous cells, checked for cancerous cells in the stool and examined the stomach by PET and CT scans—all with negative results. Yet once the stomachs were removed and new tests conducted, doctors found hundreds of early tumors in nine of the cases—the six at Stanford and three others. The remaining two cases were not yet available for review by doctors at Stanford.
What these results tell Ford is that without a gastrectomy those tumors might have spread to other organs and become untreatable by the time they were discovered. He said these results highlight the importance of removing the stomach in people with the CDH1 mutation rather than relying on screening to catch the cancer in time to save the person's life.
Ford is preparing a paper to alert the genetics community about his results. It could help other families who carry the mutation have an easier time getting insurance and institutional approval for their prophylactic surgeries as well as guide genetic counselors as they discuss options with patients.
Removing a stomach is major surgery, but the Bradfield cousins have no regrets. "The way I approach life is different now," Slabaugh said. "I don't have stress anymore. Why should I?"
During the surgery, Norton attached the bottom of the esophagus to the intestine, eliminating the stomach altogether. Without a stomach, some foods that require a long time to digest, such as salads, fall off the menu entirely. Most other foods are OK in small quantities.
Linda Bradfield said that after a slow start immediately following the surgery, she now eats almost anything. "You learn a different eating pattern," she said. "You learn to chew, chew, chew."
Instead of eating three main meals, the cousins spread small meals throughout the day. "When I go out to dinner, one meal order can last three meals," said Diane Sindt, one of the three sisters who had surgery on subsequent days. "My dates love it." She said she can no longer run only because she can't eat enough food to keep weight on.
The Bradfield cousins hope their experience can help others to get help. "Anybody with cancer in the family needs to go to a genetic counselor," Slabaugh said.
Linda Bradfield summed it up: "Living without a stomach isn't as bad as living with the uncertainty." For her and for others with a genetic risk of disease, a genetic legacy no longer writes the family's history.
Primer on genetic counselingGetting genetic counseling amounts to more than a test for a mutation. According to Nicolette Chun, genetic counselor at the Stanford Cancer Genetics Clinic, before a person decides to undergo testing, the counselor should compile a family history to identify possible disease patterns. If the history matches known cancer patterns, the counselor can help as follows: