April 27, 1994
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Joann Rodgers
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In a classic case of "what might have been," researchers at Johns Hopkins have shown, using cells from the late senator and vice president, Hubert H. Humphrey, that a novel molecular technique has the potential to diagnose cancers years before they become invasive and cause death.

With permission of Humphrey's widow, Muriel Humphrey Bro the researchers investigated his bladder cancer and other tissue samples that were on file at Hopkins and elsewhere, and were taken at various intervals during his illness.

The report, which appears in today's New England Journal of Medicine, emphasizes the power of a new cancer screening technique based on detecting cancer specific mutations. "With it, we can detect rare mutant cells hidden among thousands of normal ones, somewhere on the order of one in 10,000," says pathologist Ralph H. Hruban, M.D., who with molecular oncologist David Sidransky, M.D., co-authored the report. The technique was originally developed by Sidransky and Clayton Professor of Oncology, Bert Vogelstein, M.D.

"Had Humphrey known that he had an aggressive bladder cancer in 1967, he almost certainly would have withdrawn from the presidential race," the report says.

Funding for the work came from Oncor Inc., a Maryland biotech firm that manufactures genetic probes used in the technique.

"Bladder cancer is especially insidious," says Hruban, 'because sometimes it fails to cause symptoms, such as blood in the urine or increased frequency of urination, until it's advanced." The current best test for it, urine cytology, involves examining bladder cells that have sloughed off into the urine. But, the researchers say, false negatives aren't uncommon and the test relies heavily upon the expertise of the pathologist examining the cells.

In 1967, when he was vice president, Humphrey entered Bethesda Naval Hospital after noticing blood in his urine. Doctors then collected bladder cells that had sloughed off into his urine and did an internal examination of his bladder. An extremely small spot showed cell irregularities, but no cancer was found. The doctors sent samples of the urine cells and biopsy slides to noted pathologists for confirmation, including one at Hopkins. Though there was some disagreement, the consensus of Humphrey's physicians was one of watchful waiting.

Two years later, biopsies revealed in situ carcinoma, a preinvasive state. Then in 1973, the biopsy report was "borderline malignancy," for which Humphrey received radiation and localized chemotherapy. In 1976, his physicians diagnosed invasive bladder cancer. During subsequent surgery to remove the bladder, pathologists found the cancer had spread to the lymph nodes. Humphrey died on January 13, 1978.

For the current study, the Hopkins researchers obtained Humphrey's preserved tumor and focused on areas rich in malignant cells. Using the innovative technique, PCR, which allows researchers to make multiples of what may be very scarce genes, Peter van der Riet M.D., in Sidransky's lab isolated and amplified portions of the p53 gene from the tumor cells.

P53 is a gene well-known for involvement in a variety of cancers including breast and colon cancer. It has a normal role in suppressing cell division, but, when mutated, contributes aggressively to tumor development.

Upon close examination, the researchers found a very simple but specific mutation in the p53 gene, in an area they referred to as codon 227. The mutation wasn't present in the non-cancerous portions of Humphrey's bladder," says Sidransky.

The researchers then turned to the early urine cytology samples from 1967, and again used PCR to make investigable amounts of the p53 gene. When they applied a tailor-made molecular probe -- a "homing device" of DNA that combined specifically with Humphrey's mutation at codon 227 - the probe pointed out a small amount of the rare mutant p53.

"Remarkably, the cells harboring p53 mutations in Humphreys urine were detectable nine years before he underwent bladder removal, six years before be received any therapy and at a time when cancer could not be identified grossly in his bladder," says Hruban.

The idea of combining PCR with a probe to zero in on mutations provides "potentially the most sensitive screening device available for cancer," Sidransky says. Other techniques exist for cancer screening, yet they're primarily based on detecting abnormal proteins or other byproducts of established cancer, he adds.

"Unfortunately, the particular p53 sequence that's mutated in Humphrey's cancer isn't found in all bladder cancers," says Hruban. "Because there are so many different p53 mutations, it would be very costly and time-consuming to screen whole populations," he adds. Also, p53 mutations appear only in about 60 percent of bladder cancers.

"There's a strong possibility that other genetic changes may be found that are both specific for cancer and easier to test for," says Hruban. 'Then," adds Sidransky, "the technique should be more useful in detecting cancers early, when they're most curable."

The other researcher in the project is Yener S. Erozan, M.D.

-- JHMI --
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