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The Mormans' genetic legacy.


A study of Mormon families reveals definite evidence that heredity plays a major role in the formation of colon cancer.

Salt Lake City, Utah--When Brigham Young led the Mormons across the jagged Wasatch Mountains and into this desert basin about 140 years ago, he never could have prophesied the legacy they would leave to modern science. By studying the unusually large Mormon families who reside near here, scientists today are beginning to crack the most basic riddles of human illness and now claim to have resolved a debate that has consumed cancer researchers for years.

In a study of the Mormons, scientists at the University of Utah say they have discovered the first definitive evidence that heredity plays a major role in a common and often fatal type of cancer. They claim that colon cancer, which strikes more than 100,000 Americans a year, occurs only in people who inherit a particular gene from their parents that predisposes the children to the cancer. Those people who don't inherit the gene run only the slimmest risk of contracting the disease; perhaps, say the researchers, they run no risk at all.

Chance to Predict Cancer

The scientists, whose study is likely to send shock waves through the cancer research field, say the gene doesn't itself cause cancer. Instead, it is associated with the development of certain polyps--mushroom-like clumps of tissue in the bowel--which, because of still-unknown circumstances, may turn cancerous. Because the researchers don't yet know this gene's exact identity, their forthcoming report is expected to spark a worldwide race to discover a chemical "marker" to help locate the gene in the human body.

"Most colon cancer is detected only when the disease already has progressed dangerously," says Mark Skolnick, the lead scientist for the Utah research. "With a marker we'll be able to predict for the first time with a simple blood test who is at risk. By monitoring these people, the polyps can be found and removed before they become cancerous. That's a measure of prevention far better than anything we have now."

Skolnick's study most certainly will draw fire, since its findings contradict the prevailing belief among most cancer experts that only 5 percent to 10 percent of colon-cancer cases are due to genetic factors. The rest, they say, occur not because of heredity but because of some environmental factor, such as a diet high in animal fat.

A Special Laboratory

The new study's authors concede that their conclusion is "radical" and that their findings won't be easily reproduced outside this state. "If it weren't for the uniqueness of the people of Utah, this study wouldn't even have been undertaken," says Randall Burt, a gastroenterologist and member of the research team.

Indeed, evidence of a predisposing cancer gene is one of the more startling in a recent series of gene discoveries made possible by studies of the Mormon-based population living in and around Utah--a large, homogeneous group particularly useful to researchers doing gene studies. By following a trait as it flows through several generations and across vast branches of a family, scientists can see whether it "segregates" in a pattern that is probably due to the inheritance of a gene. The more extensive the family, the more statistically accurate this analysis.

"If you want to see, for instance, if a susceptibility to breast cancer is inherited, the first thing to do is look at siblings," Skolnick says. "If the families you are looking at average two or three sisters, there's little likelihood you'll see more than one case of cancer even if something is being inherited. But if there are five, six, or seven sisters, the chances of seeing a cluster of cancer increases. And if the same occurs among siblings in other branches of the family--well, then you can begin to make statistical assumptions that this isn't haphazard but is due to something being inherited."

Human pedigrees large enough for such study are highly valued by geneticists because, quite simply, they are rare. But in Utah, scientists in the past few years have identified dozens of clans with extensive bloodlines.

"Nowhere in the world is there a collection of people as ideal for current genetics research as the Mormons," says Ray White, co-chairman of human genetics at the University of Utah.

The million or so Mormons here--some of whom have thousands of members of their extended families living nearby--are mostly descendants of about 20,000 pioneers who trudged across the mountains to create a "kingdom of God." And right from the beginning, "the Mormon leaders did two things for which geneticists will be forever thankful," Skolnick says.

For one, they encouraged the formation of huge families as a way to quickly build the church. Over the past 100 years, Mormon couples have averaged about eight children each; today, the Mormon birth rate of about 28.6 live births per thousand people is double the U.S. average. Second, the Mormons created a church ritual that involved keeping track of one's ancestors, a practice that has led to the creation of extensive genealogical records.

In 1974, Skolnick, one of the first academics to combine an interest in computers and genetics, was recruited by the University of Utah to translate these family genealogies into a data base that could be cross-referenced with a registry of cancer cases in the state. His goal was to statistically determine whether certain cancers occurred frequently in some families and not in others--a phenomenon that, to date, had only been reported anecdotally.

By 1981, he and several colleagues had found clustering not only of breast and colon cancers but also of cancers of the prostate, lung, colon, cervix, and stomach. The researchers, however, were stumped: groups of colon-cancer incidents were evident, but a responsible (and trackable) gene wasn't.

Then, Skolnick held a fortuitous conversation in 1981 with Dr. Burt, who was studying colon problems. Skolnick described a family he had recently found in which two brothers and an uncle had colon cancer. Dr. Burt immediately suggested looking at whether middle-aged members of the family had polyps, since all colon cancers arise first from these growths.

Kindred 1002

Dr. Burt had assumed that a predisposition to growing polyps was inherited, but until he spoke with Mr. Skolnick he hadn't known there was a way to prove it. Skolnick, in turn, saw a chance to prove his genetic-inheritance theory: If he couldn't immediately show that a specific gene was causing the cancer, at least he could prove that polyps, which might later turn cancerous and could be tracked, were inherited.

The researchers called in healthy members of the Mormon family with the cancer clustering and examined them with a fiber-optic device inserted through the bowel that produces images of the inside of the colon.

By 1984, the researchers had studied 191 relatives, known as Kindred 1002. Separately, they looked at 132 spouses of family members, a group whose bloodline was unrelated to the kindred and who could be used as a control group. Adenomatous polyps, the type that can progress to cancer, were found in 21 percent of the kindred members and only 9 percent of the spouses--a finding that strongly suggested that polyp growth was inherited.

To prove the finding wasn't an anomaly distinct to that family, the researchers began looking for similarly large families. By studying Mr. Skolnick's data base and hospital records, the scientists identified families in which two siblings had colon cancer and in which they suspected that a predisposition to the disease was being inherited. By last year, the researchers had 35 families under study. They expect to eventually examine hundreds of members of at least 50 families.

Vast Clan

In Kindred 1002 alone, the scientists have examined 350 members. "And that's just a fraction of the descendants of an original pioneer," says Mr. Skolnick, noting that this single pioneer's descendants probably number about 10,000. "The [family] founder had 18 children and one of the children had four wives," he says. "If he passed a predisposing cancer gene, we'll be able to track it."

In further studies the research team found that polyp growth in the different kindreds occurred at almost double the rate of the spouses. Equally significant, a computerized analysis found that the pattern in which the trait appeared within families strongly suggested the presence of a common gene. Moreover, the researchers found polyps in a large portion of their subjects, indicating, they say, that the predisposition to colon cancer is a common one, carried by about one-third of the total U.S. population.

"That means one-third of Americans stand some risk of developing colon cancer, while the other two-thirds probably aren't at risk at all," Skolnick says. If the predisposing gene or, by using biotechnology, a marker indicating its presence can be identified, researchers will be able to tell people which group they are in. Also, by studying those with the gene who develop cancers, researchers will have a powerful tool to help identify what--a type of diet, perhaps--turns these polyps malignant.

In the meantime, the findings of other scientists studying colon cancer may help in the search for the polyp growth gene. Over the past year, two teams of researchers, one at Johns Hopkins University and the other in London, have found that cells taken from colon cancer tumors are missing tiny bits of DNA--possibly even tiny bits of genes--on two different chromosomes. The Utah research group expects to focus on one of these chromosomes as the location of a mutant gene that may involve cancerous polyp growth.

A 12-Year-Old's Cancer

Meanwhile, Skolnick has linked up with two other physician-researchers who are using a similar strategy to look for predisposing genes for breast cancer and melanoma, the cancer of the skin. Already, Laurence Meyer, a research dermatologist at Salt Lake City Veterans Administration Medical Center, believes a collection of certain otherwise-harmless moles on an individual's skin may signal melanoma and therefore may serve as a trait that can be tracked through families just like polyps.

As a side benefit, the melanoma research is already helping Dr. Meyer identify--and warn--people who did not know they ran a risk of developing cancer. Recently, for instance, Dr. Meyer was examining benign skin moles on the members of a Mormon family in which a cluster of three melanoma cases had been found. While looking at the 12-year-old grandnephew of one of the melanoma victims, "I found a mole that already had advanced to an early stage of cancer," Dr. Meyer said. Through removal of the mole, the cancer was stopped.

"I was shocked," says Gretl Crapo, the boy's mother. "I was even more surprised when Dr. Meyer told me that melanoma seemed to run in my family." By the time she and her children were examined, Dr. Meyer had seen 100 members of the family. Unbeknownst to her, Dr. Meyer had found out that several siblings of Mrs. Crapo's father, along with a cousin and a second cousin, had died of melanoma. The information has "convinced us all to use sunscreen, not just when we go to the beach but all the time," she says.

Like many other Mormon families, Mrs. Crapo's family--known as Kindred 152--is extensive. Her mother was one of eight siblings and her father was one of nine siblings. Moreover, her parents had nine children, and many of her parents' siblings had seven, eight, and nine children. Mrs. Crapo and her husband, Ronell, have five children.

All of which is good news to Skolnick and his colleagues, who expect to continue studying the Mormon families. "You know there must be a reason some people get lung cancer and others don't," he says. He says his success so far examining colon cancer leads him to believe there are physical traits caused by predisposing genes for most cancers. "It's going to be hard finding the traits," he adds, "but at least now we have an incentive for looking."

PHOTO : Mormon families like the Wilsteds (below) are a boon to medical research. The Mormon birth

PHOTO : rate, which is double the national average, coupled with the church's practice of

PHOTO : compiling extensive genealogical records, has created a plentiful playground for

PHOTO : scientists trying to track genetic diseases.
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Title Annotation:heredity and colon cancer
Author:Waldholz, Michael
Publication:Saturday Evening Post
Date:Nov 1, 1988
Previous Article:Hips, hips away!
Next Article:Not all the turkeys are in the oven.

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