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Prostate link was all in the families Hopkins scientists culled a 'gold mine' of genetic histories

The discovery by Johns Hopkins scientists of a hereditary link to prostate cancer was not simply a triumph of brains -- but a logistical feat that depended on the telephone, overnight mail, genealogical charts and sheer persistence.

It was also a demonstration that ordinary people yielding vials of blood and family histories can play a pivotal role in the slow and often tedious grind of science. Ninety-one families -- 600 people from three nations -- provided the raw material for a discovery that could soon lead to a test for genetic susceptibility.

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"We had what no one else had -- the families," said Dr. William B. Isaacs, a Hopkins molecular biologist who shared in making the announcement Thursday. "They were our gold mine."

The families were recruited because they were hit hard by prostate cancer, with afflicted sons, cousins, fathers and uncles scattered across the generations. When scientists scanned their DNA for evidence of a common defect, they struck pay dirt: a marker on the first chromosome that almost surely will point the way to the faulty gene.

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Dr. Patrick Walsh, the surgeon who heads Hopkins' Brady Urological Institute, became famous for developing a way to remove diseased prostates without sacrificing sexual function or urinary control. But his interests transcend surgery, encompassing such questions as what causes the disease and whether some men are born predisposed.

Doctors had long observed that the disease seems to run in some families. Utah's Mormons, among the most ardent of the world's genealogists, reported in medical literature that they had noticed this in the family trees of church members.

But nobody had determined whether clusters were because of genetic inheritance or a common environmental exposure such as diet or pollution.

That task would be left to Walsh, who in 1986 saw a 49-year-old cancer patient with a compelling family history. Every man in his immediate family had died of the disease -- his father, his father's three brothers and his grandfather.

The man sparked more than curiosity. Walsh mobilized his department to find the genes, if any, that pass the disease from generation to generation.

Walsh took family histories of 700 patients who had come to him for the removal of diseased prostates. He discovered that men with one or more first-degree relatives -- fathers and brothers -- had an elevated risk of prostate cancer. The greater the number of afflicted relatives, the higher a man's risk.

The disease did not run in most of the families. But where it did, it appeared in different generations, and it didn't matter where they lived. This suggested that the disease was a matter of inheritance. An environmental cause would probably be limited to geographic regions or certain generations.

From this study, he estimated that 10 percent of all prostate cancers are inherited. But to find the gene or genes, he would need a larger collection of families.

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Four years ago, his department mailed letters to the 8,000 physicians belonging to the American Urological Association, asking them for help in obtaining blood samples and histories from patients who had at least three affected family members.

Sally Isaacs, a behavioral scientist who had spent several years studying hereditary links to learning disabilities, was chosen to command a logistical enterprise that could challenge the Census Bureau.

Her interest was more than casual. Her father was a prostate cancer survivor. Her husband, Dr. John Isaacs, was a Hopkins tumor biologist studying ways to control the growth of prostate cancers. And his brother, William Isaacs, was a molecular biologist looking at the genetic basis.

"The brothers are constantly talking this stuff," Sally Isaacs said. "That's all I hear."

Walsh's appeal generated a huge response, as did his appearance on "The Phil Donahue Show" and coverage in mass-market publications such as Parade.

Some 2,500 families responded, enough to give Sally Isaacs the luxury to skim those in which prostate cancer had taken the heaviest toll. She chose 91 families -- 79 from the United States and Canada and 12 from Sweden. (The Swedes were recruited at Umea University.)

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She telephoned the patients and their relatives, asking them to answer questionnaires with details about their health, occupation and family history. The patients later went to their local doctors and submitted blood samples that were sent to Hopkins by overnight mail.

"We were very structured," she said. "The blood samples could only be drawn on Monday, Tuesday or Wednesday. That would allow 24 hours to get back to us before the weekend when the lab closed.

"I could depend on getting one or two bloods every day. And there were phone calls, many many phone calls."

One of the patients was Henry Hicks, a high school principal in Winston-Salem, N.C. Four years ago, his 68-year-old father was diagnosed with prostate cancer. Tests showed the cancer had spread, so it was useless to operate. He soon died.

"Call it divine inspiration," said Hicks, a deeply religious man who is now 43. "But without any motive it just hit me in the eye: I might as well get tested, too."

His local doctor, performing a digital rectal exam, felt a hard spot that suggested a possible malignancy. Although a PSA blood test was normal, a biopsy showed microscopic evidence of cancer. He decided to have it removed, and his doctor scheduled an appointment with Walsh.

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Hicks says he has suffered no side effects since the operation and has remained free of cancer. The experience turned him into a zealous advocate of prostate cancer screening and an eager participant in Walsh's study.

He drove around the countryside, stopping at the homes of family members in an area south of Winston-Salem.

"They got the faith," said Hicks. "But it wasn't all rosy. There were confusions, doubts and some resentments. I reminded them that I had two boys, and I had promised the Lord that I would work for him and that's what I was doing."

In the end, most participated.

What Hicks learned disturbed and amazed him.

His father had seven brothers. Six are now dead -- five of them victims of prostate cancer. The sixth died of a massive heart attack, but an autopsy showed that he, too, had the disease. Several cousins agreed to get tested, and four were diagnosed with cancer.

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Including Hicks, 13 men spanning three generations had the disease. But until he began asking, he did not have an inkling that his family was at risk.

"My parents came from the old school, so it's not your typical dinner conversation to discuss this because of the seeming necessity for privacy," Hicks said. "I can recall them saying that someone had a problem in his lower abdomen or his private area. But they never went into details."

In his office, William Isaacs holds 91 pages, each containing a family genealogy. Circles are women; squares are men. Shaded squares are cancer cases; slashes are deaths.

These are the families that supplied the blood and told the stories that led scientists to their mark. Now that they have found the region where the gene is located, they expect to isolate the gene within a few years.

Narrowing the human genome to a single trouble spot is, of course, difficult to comprehend. Dr. Donald S. Coffey, a Hopkins oncology professor, compares it to finding a misspelled word in 17 complete sets -- or 380,490 pages -- of the Encyclopedia Britannica.

By finding the marker, they have narrowed the search to 400 pages.

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"It's nice but it's really humbling," said Sally Isaacs. She noted that most prostate cancers are not inherited and that scientists still don't know how to cure advanced cases. "There's a long way to go."

Pub Date: 11/23/96


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