A cancer mutation's Colonial roots
Researchers track a legacy of disease
When Mr. and Mrs. George Fry landed on the shores of Massachusetts not long after the Pilgrims, they carried with them a secret that remained hidden for nearly four centuries.
Their genes harbored a quirk that would travel through 16 generations of Americans, leaving a legacy of colon cancer. Now a Utah scientist, herself a descendant of Mayflower voyagers and Benjamin Franklin, has discovered the Fry family history.
In an example of crack scientific sleuthing, the University of Utah researcher and colleagues mined a trove of cancer records and a sprawling genealogical archive to uncover the source of a genetic mutation responsible for a rare form of colon cancer. Modern-day genetic fingerprinting identified far-flung relatives with this defect, and the team then traced the family tree back in time, past the Revolutionary War, to find their common ancestors.
They finally arrived at Weymouth, when colonists were only beginning to stake their claim to a new land. There, they found the Frys, who had decamped from their home in Somerset, England, sometime between 1624 and 1640, harboring hopes and the seeds of disease.
The search was driven by more than historical curiosity, specialists say. The work shows the power of genetics and genealogy to identify family members who share mutations so that they can be spared from a potentially deadly disease.
Already, the discovery, detailed last week at the national meeting of the American Chemical Society, appears to be saving 21st-century lives. Physicians have tracked down distant relatives of the Frys and offered those who have the mutation testing for early signs of colon cancer and preventive treatment. The result: cases of the kind of colon cancer spawned by the mutation have nearly vanished in Utah.
"The point is, there are hereditary components to diseases and you need to be aware of what your family history is," said Dr. Daniel Chung, clinical director of the Gastrointestinal Cancer Genetics Program at the Massachusetts General Hospital Cancer Center. "And it's just kind of a cool story that they can trace this mutation back."
The detective story began more than a decade ago, when University of Utah scientists discovered that members of a Utah family battling colon cancer carried a specific mutation in a gene know by the acronym APC.
"Over about the next 10 years," said Deb Neklason, a molecular geneticist at the university's Huntsman Cancer Institute and a Mayflower descendant, "they brought in tons and tons of family members to try to figure out who had the genetic change." Those who did had colonoscopies performed to look for cancer.
At the same time, a doctor in upstate New York was treating patients from a family harboring the same genetic profile.
So the Utah scientists - led by Neklason, who describes herself as "a professional geneticist and an amateur genealogist" - started culling genealogical and medical records. They were hunting for clues that might tell them whether the Utah and New York families were related and, if so, which branches were at risk of developing the form of colon cancer, called attenuated familial adenomatous polyposis.
There is no place better to do that than Utah, headquarters of the Mormon church, which embraces genealogy with unparalleled fervor and keeps detailed family lineages in an online database. That interest has also made the state receptive to maintaining a cancer registry linked to family histories, which it has done since 1966.
Genetic analysis showed the mutation was not occurring randomly, so researchers were sure it was a family affair. The scientists began linking current-day carriers to their forebears in a process akin to climbing a ladder, with the living heirs as the first rung.
For example, if two modern-day first cousins were identified as carriers, that meant there had to be a mutual grandparent who was the source of the genetic trait. In similar fashion, the researchers were able to identify shared ancestors among mutation carriers from earlier generations, even though they have no surviving genetic material available for testing.
The researchers concluded the Utah and New York families were related, both descended from the Frys.
The researchers also sketched a quintessential map of American migration, showing how a couple wed in England in 1615 landed in the wilderness of Massachusetts, with one of their offspring marrying in Weymouth in 1640. Later generations then made a westward trek.
The Utah branch, they discovered, descended from a daughter of the Frys; her heirs embarked on their westward migration in the mid-1800s. The New York branch descended from the Frys' son.
Fifteen US families have been identified with the mutation, with as many as 500 adults carrying the trait. Adults with that genetic signature who don't undergo colonoscopies or removal of precancerous polyps have a 2 in 3 chance of developing colon cancer by the age of 80, substantially higher than the general population. About three dozen descendants nationally have been diagnosed with colon cancer related to the mutation. Other genetic mutations in addition to the one linked to the Frys can also cause this form of colon cancer.
"For these genetic syndromes," said Dr. Jeffrey Meyerhardt, a gastrointestinal oncologist at Dana-Farber Cancer Institute, "it's an important piece of scientific work to be able to trace back where things start. We can often understand more about the mutations and the syndromes they cause and learn if things changed over generations. Do people in subsequent generations have more cancer?
"That," he said, "is why history matters."
Stephen Smith can be reached at firstname.lastname@example.org.